This document reviews the mechanisms of antibiotic resistance and tolerance in Streptococcus pneumoniae. It discusses how S. pneumoniae has developed three main mechanisms to resist antibiotics: preventing antibiotic access to targets, inactivating antibiotics, and altering antibiotic targets. Specifically, it describes how mutations in penicillin-binding proteins can reduce affinity for beta-lactam antibiotics like penicillin. It also explains how mutations in DNA gyrase and topoisomerase genes can confer resistance to fluoroquinolones by altering their targets. Recent studies on antibiotic tolerant mutants revealed new insights into controlling bacterial cell death.
A trends of salmonella and antibiotic resistanceAlexander Decker
This document discusses trends in Salmonella and antibiotic resistance. It provides background on Salmonella, including its classification and the historical perspectives of its discovery. It then discusses definitions of antimicrobials and antibiotics, and the mechanisms by which Salmonella develops resistance to various classes of antibiotics, including aminoglycosides, beta-lactams, chloramphenicol, quinolones, tetracyclines, sulfonamides and trimethoprim. Resistance occurs through modification or destruction of antibiotics, efflux pumps, modification of antibiotic targets, and decreased membrane permeability.
This document discusses antimicrobial resistance in Libya. It finds resistance is a serious problem that is increasing, including emerging resistance to newer drugs. Many bacteria isolated from clinical and other sources in Libya show high resistance percentages to various antibiotics. Resistance appears related to easy over-the-counter antibiotic access without prescription, improper hospital usage, and uncontrolled animal antibiotic use. Urgent action is needed to regulate antibiotic sales and usage, educate on proper clinical use, control hospital infections, and regulate non-human antibiotic use to address this growing resistance issue in Libya.
The document discusses evolving strategies in antibiotic discovery and development. It focuses on how chemical modification of natural product scaffolds through semi-synthesis has dominated antibiotic development and led to many successful drugs. However, rising drug resistance requires new innovations, like developing antibiotic adjuvants to preserve existing drugs or expanding chemical diversity through synthetic biology or new techniques to mine antibiotic-producing organisms. Understanding antibiotic chemical properties and harnessing both synthetic chemistry and natural product discovery will be important to address the growing need for new antibiotics.
This document discusses optimizing therapy for vancomycin-resistant enterococci (VRE). It notes that enterococci infections have significantly increased in hospitals over the past two decades, often due to multidrug-resistant strains. Treatment options for VRE infections were limited until the development of newer antimicrobials like linezolid and daptomycin. However, resistance to even these newer drugs has emerged. The optimal treatment of VRE infections, especially endocarditis, remains unclear due to the lack of comparative clinical trials and the emergence of resistance to newer antimicrobials. Non-antimicrobial measures can help reduce treatment needs and resistance risk.
Plasmids have found important applications in biotechnology especially in recombinant DNA technology. However, most antibiotic resistant genes are transferred from one organism to the other through horizontal transfer of gene via this vehicle.
1. The document discusses mechanisms of antibiotic resistance, focusing on beta-lactam resistance. It describes how bacteria can acquire resistance through mutation or horizontal gene transfer of mobile genetic elements carrying resistance genes.
2. Major mechanisms of beta-lactam resistance in bacteria involve altering drug targets, enzymatically inactivating antibiotics, reducing drug accessibility, or increasing drug efflux. The document reviews resistance in key pathogens like MRSA, VRE, and carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii.
3. It also briefly discusses strategies to overcome resistance, like developing new antibiotics and finding ways to improve drug delivery through cell membranes.
mechanism of resistance of antibiotics, ESBL, b lactums, enterobactericae, metallobactums, carbapenemases, types of mechanism of resistance, history of antibiotics and resistance
A trends of salmonella and antibiotic resistanceAlexander Decker
This document discusses trends in Salmonella and antibiotic resistance. It provides background on Salmonella, including its classification and the historical perspectives of its discovery. It then discusses definitions of antimicrobials and antibiotics, and the mechanisms by which Salmonella develops resistance to various classes of antibiotics, including aminoglycosides, beta-lactams, chloramphenicol, quinolones, tetracyclines, sulfonamides and trimethoprim. Resistance occurs through modification or destruction of antibiotics, efflux pumps, modification of antibiotic targets, and decreased membrane permeability.
This document discusses antimicrobial resistance in Libya. It finds resistance is a serious problem that is increasing, including emerging resistance to newer drugs. Many bacteria isolated from clinical and other sources in Libya show high resistance percentages to various antibiotics. Resistance appears related to easy over-the-counter antibiotic access without prescription, improper hospital usage, and uncontrolled animal antibiotic use. Urgent action is needed to regulate antibiotic sales and usage, educate on proper clinical use, control hospital infections, and regulate non-human antibiotic use to address this growing resistance issue in Libya.
The document discusses evolving strategies in antibiotic discovery and development. It focuses on how chemical modification of natural product scaffolds through semi-synthesis has dominated antibiotic development and led to many successful drugs. However, rising drug resistance requires new innovations, like developing antibiotic adjuvants to preserve existing drugs or expanding chemical diversity through synthetic biology or new techniques to mine antibiotic-producing organisms. Understanding antibiotic chemical properties and harnessing both synthetic chemistry and natural product discovery will be important to address the growing need for new antibiotics.
This document discusses optimizing therapy for vancomycin-resistant enterococci (VRE). It notes that enterococci infections have significantly increased in hospitals over the past two decades, often due to multidrug-resistant strains. Treatment options for VRE infections were limited until the development of newer antimicrobials like linezolid and daptomycin. However, resistance to even these newer drugs has emerged. The optimal treatment of VRE infections, especially endocarditis, remains unclear due to the lack of comparative clinical trials and the emergence of resistance to newer antimicrobials. Non-antimicrobial measures can help reduce treatment needs and resistance risk.
Plasmids have found important applications in biotechnology especially in recombinant DNA technology. However, most antibiotic resistant genes are transferred from one organism to the other through horizontal transfer of gene via this vehicle.
1. The document discusses mechanisms of antibiotic resistance, focusing on beta-lactam resistance. It describes how bacteria can acquire resistance through mutation or horizontal gene transfer of mobile genetic elements carrying resistance genes.
2. Major mechanisms of beta-lactam resistance in bacteria involve altering drug targets, enzymatically inactivating antibiotics, reducing drug accessibility, or increasing drug efflux. The document reviews resistance in key pathogens like MRSA, VRE, and carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii.
3. It also briefly discusses strategies to overcome resistance, like developing new antibiotics and finding ways to improve drug delivery through cell membranes.
mechanism of resistance of antibiotics, ESBL, b lactums, enterobactericae, metallobactums, carbapenemases, types of mechanism of resistance, history of antibiotics and resistance
The document discusses efflux pumps in bacteria. It begins by noting that efflux pumps contribute to antibiotic resistance and are involved in bacterial pathogenesis. There are five major families of efflux transporters - ATP-binding cassette (ABC), resistance-nodulation-division (RND), small multidrug resistance (SMR), major facilitator superfamily (MFS), and multidrug and toxic compound extrusion (MATE). The RND family is especially effective at generating multidrug resistance in gram-negative bacteria. Efflux pumps export various substrates like antibiotics, toxins, and metabolites using secondary active transport driven by proton or sodium ion gradients. Inhibitors of efflux pumps have potential to restore drug susceptibility in multidrug-
This document summarizes key information about aminoglycoside antibiotics:
1) Aminoglycosides act by binding to bacterial ribosomes and impairing protein synthesis, but their use is limited by the emergence of resistance.
2) Resistance can occur via decreased drug accumulation in bacteria or expression of aminoglycoside-modifying enzymes. These enzymes chemically modify the drug, preventing ribosome binding.
3) A large diversity of modifying enzymes exists, and bacteria can acquire new resistance genes rapidly via mobile genetic elements. This complexity has made predicting effective aminoglycoside use difficult.
This document summarizes various structures and mechanisms in prokaryotic cells. It discusses biofilms, cell walls, membrane transport systems, secretion systems, flagella, pili, DNA transfer through transformation, transduction, and conjugation, as well as endospore formation. Bacterial adaptation is enabled by horizontal gene transfer including plasmids, transposons, and pathogenicity islands which facilitate the acquisition of virulence factors and antibiotic resistance.
The document discusses various aspects of antimicrobial drug resistance. It begins by defining antimicrobial drugs and antimicrobial resistance. It then covers the genetic basis of resistance including chromosome-mediated resistance, plasmid-mediated resistance, and transposon-mediated resistance. Specific mechanisms of resistance to different drug classes such as penicillins, cephalosporins, carbapenems, and quinolones are described. Non-genetic bases of resistance and methods to test antibiotic sensitivity and combat resistance are also summarized.
This document discusses the growing problem of antibiotic resistance around the world. It provides statistics on antibiotic resistance in the US, Europe, and Middle East. It describes "superbugs" emerging in India that are resistant to many antibiotics. Ongoing research is working to understand the evolution of resistance and improve databases tracking resistance. The ND4BB initiative is working across Europe to address antibiotic resistance through projects that create clinical networks, study how resistance spreads between bacteria, and develop new drug discovery platforms. Experiments are described that use different antibiotics to study resistance development and cross-resistance at a genomic level. Databases like ARDB track known antibiotic resistance genes.
This document discusses the mechanisms of action and resistance of quinolone antibiotics. It begins by providing background on quinolones and their targets, bacterial type II topoisomerases. It then explains how quinolones work by stabilizing cleavage complexes of gyrase and topoisomerase IV, converting them into cellular toxins. This poisoning mechanism leads to DNA breaks and cell death. The document discusses three main mechanisms of quinolone resistance: target-mediated mutations in gyrase/topoisomerase IV, plasmid-mediated resistance factors, and efflux pump overexpression. It concludes by discussing recent insights into quinolone-enzyme interactions and how resistance mutations function.
This document discusses antibiotic resistance and its mechanisms. It provides four main mechanisms of antibiotic resistance: bacteria producing inactivating enzymes, synthesizing modified drug targets, reducing drug permeability, and actively exporting drugs. The genetic basis includes chromosomal mutations, plasmids, and transposons transferring resistance genes. Specific resistance mechanisms are described for several drug classes like beta-lactams, aminoglycosides, tetracyclines and others. Nongenetic resistance factors include bacteria being in abscesses, resting states, or losing cell walls. Overuse and misuse of antibiotics can select for resistant bacteria.
Development of Multiple Antibiotic Resistance in Microbes (Microbial Genetics) Zohaib HUSSAIN
This document discusses multidrug resistance in bacteria. It summarizes that bacteria can develop multidrug resistance through two main mechanisms: 1) Accumulating multiple resistance genes on plasmids or transposons, with each gene conferring resistance to a single drug. 2) Increased expression of multidrug efflux pumps that can extrude a wide range of drugs. The document then reviews various molecular mechanisms that can generate drug resistance, including mutating drug targets, enzymatically inactivating drugs, modifying drug targets from other species, and preventing drug access through efflux or impermeable barriers.
Bacterial resistance mechanisms and new trends for resistance overcoming Mohammed Fawzy
This document discusses bacterial resistance and its mechanisms. It begins with an overview of the increasing issue of antimicrobial resistance worldwide. It then covers the origins of resistance as either intrinsic or acquired through mutation or horizontal gene transfer. The major mechanisms of acquired resistance are expressed genes coding for altered drug targets, enzymatic drug inactivation, efflux pumps, and biofilms. Factors promoting resistance include antibiotic misuse in medicine and agriculture as well as a lack of new drug development. The consequences are serious infections that are difficult to treat.
FLOW OF THE SEMINAR
1. Definition – antibiotic resistance, Multi-resistance, cross-resistance in antibiotics
2. Evolution of resistance
3. Impact of resistance
4. The scenario of resistance: Global, India
5. Factors causing resistance
6. Mechanisms of resistance: Intrinsic and Acquired
7. Acquired mechanism of resistance
8. Quorum sensing
9. Mechanism of resistance in commonly used antibiotics
10. Methods for determining the resistance
11. Strategies to contain resistance
12. Antibiotic stewardship
13. Role of Pharmacologist
14. Initiatives undertaken by India to control resistance
1. Antimicrobial resistance arises through genetic mutations and the acquisition of resistance genes from other bacteria.
2. Resistance genes can be acquired horizontally via mobile genetic elements such as plasmids, leading to rapid spread.
3. Common resistance mechanisms include enzymatic inactivation of antibiotics, modification or protection of antibiotic targets, and efflux pumps that pump out antibiotics.
International Journal of Pharmaceutical Science Invention (IJPSI) inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
The document discusses mechanisms of drug resistance in malaria parasites and fungal infections. For malaria, specific genes associated with resistance to various antimalarial drugs like chloroquine, quinine, sulfadoxine/pyrimethamine are identified. Molecular markers in these genes can help detect emerging drug resistance. Phenotypic tests can also detect resistance but have limitations. Resistance mechanisms in Candida include decreased drug accumulation by efflux pumps, target site alterations of lanosterol demethylase, and developing bypass pathways. Mechanisms of azole resistance in Aspergillus include efflux pumps and modifications to cyp51 genes. The document also discusses resistance mechanisms for other antifungals, antitubercular drugs, and
Molecular mechanisms of antimicrobial resistance in bacteria Jobir Nadhi
Molecular mechanisms of antimicrobial resistance in bacteria by highlighting the aspects of antimicrobial resistance
through a discussion of:
Bacterial strategies involved in resisting antimicrobial actions and
The molecular basis for bacterial resistance to
antimicrobial actions
some note kept in phrase are completed visualizing the picture.
1) The study investigated the role of efflux pumps in clarithromycin- and moxifloxacin-resistant Helicobacter pylori strains by testing the efficacy of efflux pump inhibitors (EPIs).
2) For moxifloxacin-resistant strains, EPIs reduced the MIC more for strains with an Asp-91 mutation (73%) than an Asn-87 mutation (14%). For clarithromycin strains, EPIs reduced the MIC for 75% of strains overall.
3) The results indicate efflux pumps contribute to clarithromycin and moxifloxacin resistance in H. pylori, but their involvement may depend on specific mutations present
The document summarizes a presentation on antimicrobial drug resistance given by Dr. Manas Kr. Nath. It discusses the objectives of the presentation, which were to introduce antimicrobial drug resistance, define it, discuss its timeline and factors, mechanisms of resistance, control strategies, and conclusions. The presentation covered intrinsic and acquired resistance, genetic and biochemical mechanisms of resistance such as mutations, plasmids, conjugation, transduction, transformation, transposons, integrons, and production of antibiotic inactivating enzymes. It emphasized that antimicrobial resistance is a major global health concern.
Calprotectin (CP) is a metal-chelating protein produced by neutrophils during inflammation. CP inhibits the growth of Helicobacter pylori, a major risk factor for gastric cancer, by sequestering the metals manganese and zinc. Studies show that CP reduces the activity of H. pylori's cag Type IV Secretion System (T4SS) in a zinc-dependent manner by inhibiting T4SS pilus biogenesis. This decreases H. pylori's ability to translocate the oncoprotein CagA into gastric cells and reduce inflammation. While CP limits H. pylori growth and virulence, it also allows the bacteria to persist by modulating the inflammatory response.
Of 150 E. coli strains cultured from cattle in Europe, 3 were resistant to colistin. One strain was found to carry the mcr-1 gene, conferring plasmid-mediated colistin resistance. This strain also showed resistance to beta-lactams, florfenicol, and fluoroquinolones. Whole genome sequencing identified resistance genes and plasmids in the 3 colistin-resistant strains. The mcr-1 gene was found on a plasmid in one strain isolated in France in 2007, demonstrating the presence of this gene in livestock in Europe.
This document discusses biochemical tests used to identify and differentiate streptococci species. It describes characteristics of streptococci and how they can be classified based on hemolytic patterns on blood agar and Lancefield grouping. Key differentiation tests discussed include the bacitracin test to identify Streptococcus pyogenes, the CAMP test for S. agalactiae, optochin susceptibility and bile solubility for S. pneumoniae versus viridans streptococci, and inulin fermentation. Biochemical reactions and test results are summarized to differentiate between common streptococci.
Streptococcus is a genus of bacteria that includes several species that are pathogens. They are spherical, gram-positive cocci that can be α-hemolytic, β-hemolytic, or non-hemolytic. Important pathogenic species include Streptococcus pyogenes (group A streptococcus), a cause of pharyngitis and skin infections, and Streptococcus agalactiae (group B streptococcus), a cause of neonatal sepsis and meningitis. Enterococcus faecalis is a frequent cause of hospital-acquired infections like urinary tract infections. Viridans streptococci commonly cause infective endocarditis. Identification involves culturing samples and observing hemolysis and sensitivity to antibiotics like bac
The document discusses efflux pumps in bacteria. It begins by noting that efflux pumps contribute to antibiotic resistance and are involved in bacterial pathogenesis. There are five major families of efflux transporters - ATP-binding cassette (ABC), resistance-nodulation-division (RND), small multidrug resistance (SMR), major facilitator superfamily (MFS), and multidrug and toxic compound extrusion (MATE). The RND family is especially effective at generating multidrug resistance in gram-negative bacteria. Efflux pumps export various substrates like antibiotics, toxins, and metabolites using secondary active transport driven by proton or sodium ion gradients. Inhibitors of efflux pumps have potential to restore drug susceptibility in multidrug-
This document summarizes key information about aminoglycoside antibiotics:
1) Aminoglycosides act by binding to bacterial ribosomes and impairing protein synthesis, but their use is limited by the emergence of resistance.
2) Resistance can occur via decreased drug accumulation in bacteria or expression of aminoglycoside-modifying enzymes. These enzymes chemically modify the drug, preventing ribosome binding.
3) A large diversity of modifying enzymes exists, and bacteria can acquire new resistance genes rapidly via mobile genetic elements. This complexity has made predicting effective aminoglycoside use difficult.
This document summarizes various structures and mechanisms in prokaryotic cells. It discusses biofilms, cell walls, membrane transport systems, secretion systems, flagella, pili, DNA transfer through transformation, transduction, and conjugation, as well as endospore formation. Bacterial adaptation is enabled by horizontal gene transfer including plasmids, transposons, and pathogenicity islands which facilitate the acquisition of virulence factors and antibiotic resistance.
The document discusses various aspects of antimicrobial drug resistance. It begins by defining antimicrobial drugs and antimicrobial resistance. It then covers the genetic basis of resistance including chromosome-mediated resistance, plasmid-mediated resistance, and transposon-mediated resistance. Specific mechanisms of resistance to different drug classes such as penicillins, cephalosporins, carbapenems, and quinolones are described. Non-genetic bases of resistance and methods to test antibiotic sensitivity and combat resistance are also summarized.
This document discusses the growing problem of antibiotic resistance around the world. It provides statistics on antibiotic resistance in the US, Europe, and Middle East. It describes "superbugs" emerging in India that are resistant to many antibiotics. Ongoing research is working to understand the evolution of resistance and improve databases tracking resistance. The ND4BB initiative is working across Europe to address antibiotic resistance through projects that create clinical networks, study how resistance spreads between bacteria, and develop new drug discovery platforms. Experiments are described that use different antibiotics to study resistance development and cross-resistance at a genomic level. Databases like ARDB track known antibiotic resistance genes.
This document discusses the mechanisms of action and resistance of quinolone antibiotics. It begins by providing background on quinolones and their targets, bacterial type II topoisomerases. It then explains how quinolones work by stabilizing cleavage complexes of gyrase and topoisomerase IV, converting them into cellular toxins. This poisoning mechanism leads to DNA breaks and cell death. The document discusses three main mechanisms of quinolone resistance: target-mediated mutations in gyrase/topoisomerase IV, plasmid-mediated resistance factors, and efflux pump overexpression. It concludes by discussing recent insights into quinolone-enzyme interactions and how resistance mutations function.
This document discusses antibiotic resistance and its mechanisms. It provides four main mechanisms of antibiotic resistance: bacteria producing inactivating enzymes, synthesizing modified drug targets, reducing drug permeability, and actively exporting drugs. The genetic basis includes chromosomal mutations, plasmids, and transposons transferring resistance genes. Specific resistance mechanisms are described for several drug classes like beta-lactams, aminoglycosides, tetracyclines and others. Nongenetic resistance factors include bacteria being in abscesses, resting states, or losing cell walls. Overuse and misuse of antibiotics can select for resistant bacteria.
Development of Multiple Antibiotic Resistance in Microbes (Microbial Genetics) Zohaib HUSSAIN
This document discusses multidrug resistance in bacteria. It summarizes that bacteria can develop multidrug resistance through two main mechanisms: 1) Accumulating multiple resistance genes on plasmids or transposons, with each gene conferring resistance to a single drug. 2) Increased expression of multidrug efflux pumps that can extrude a wide range of drugs. The document then reviews various molecular mechanisms that can generate drug resistance, including mutating drug targets, enzymatically inactivating drugs, modifying drug targets from other species, and preventing drug access through efflux or impermeable barriers.
Bacterial resistance mechanisms and new trends for resistance overcoming Mohammed Fawzy
This document discusses bacterial resistance and its mechanisms. It begins with an overview of the increasing issue of antimicrobial resistance worldwide. It then covers the origins of resistance as either intrinsic or acquired through mutation or horizontal gene transfer. The major mechanisms of acquired resistance are expressed genes coding for altered drug targets, enzymatic drug inactivation, efflux pumps, and biofilms. Factors promoting resistance include antibiotic misuse in medicine and agriculture as well as a lack of new drug development. The consequences are serious infections that are difficult to treat.
FLOW OF THE SEMINAR
1. Definition – antibiotic resistance, Multi-resistance, cross-resistance in antibiotics
2. Evolution of resistance
3. Impact of resistance
4. The scenario of resistance: Global, India
5. Factors causing resistance
6. Mechanisms of resistance: Intrinsic and Acquired
7. Acquired mechanism of resistance
8. Quorum sensing
9. Mechanism of resistance in commonly used antibiotics
10. Methods for determining the resistance
11. Strategies to contain resistance
12. Antibiotic stewardship
13. Role of Pharmacologist
14. Initiatives undertaken by India to control resistance
1. Antimicrobial resistance arises through genetic mutations and the acquisition of resistance genes from other bacteria.
2. Resistance genes can be acquired horizontally via mobile genetic elements such as plasmids, leading to rapid spread.
3. Common resistance mechanisms include enzymatic inactivation of antibiotics, modification or protection of antibiotic targets, and efflux pumps that pump out antibiotics.
International Journal of Pharmaceutical Science Invention (IJPSI) inventionjournals
International Journal of Pharmaceutical Science Invention (IJPSI) is an international journal intended for professionals and researchers in all fields of Pahrmaceutical Science. IJPSI publishes research articles and reviews within the whole field Pharmacy and Pharmaceutical Science, new teaching methods, assessment, validation and the impact of new technologies and it will continue to provide information on the latest trends and developments in this ever-expanding subject. The publications of papers are selected through double peer reviewed to ensure originality, relevance, and readability. The articles published in our journal can be accessed online
The document discusses mechanisms of drug resistance in malaria parasites and fungal infections. For malaria, specific genes associated with resistance to various antimalarial drugs like chloroquine, quinine, sulfadoxine/pyrimethamine are identified. Molecular markers in these genes can help detect emerging drug resistance. Phenotypic tests can also detect resistance but have limitations. Resistance mechanisms in Candida include decreased drug accumulation by efflux pumps, target site alterations of lanosterol demethylase, and developing bypass pathways. Mechanisms of azole resistance in Aspergillus include efflux pumps and modifications to cyp51 genes. The document also discusses resistance mechanisms for other antifungals, antitubercular drugs, and
Molecular mechanisms of antimicrobial resistance in bacteria Jobir Nadhi
Molecular mechanisms of antimicrobial resistance in bacteria by highlighting the aspects of antimicrobial resistance
through a discussion of:
Bacterial strategies involved in resisting antimicrobial actions and
The molecular basis for bacterial resistance to
antimicrobial actions
some note kept in phrase are completed visualizing the picture.
1) The study investigated the role of efflux pumps in clarithromycin- and moxifloxacin-resistant Helicobacter pylori strains by testing the efficacy of efflux pump inhibitors (EPIs).
2) For moxifloxacin-resistant strains, EPIs reduced the MIC more for strains with an Asp-91 mutation (73%) than an Asn-87 mutation (14%). For clarithromycin strains, EPIs reduced the MIC for 75% of strains overall.
3) The results indicate efflux pumps contribute to clarithromycin and moxifloxacin resistance in H. pylori, but their involvement may depend on specific mutations present
The document summarizes a presentation on antimicrobial drug resistance given by Dr. Manas Kr. Nath. It discusses the objectives of the presentation, which were to introduce antimicrobial drug resistance, define it, discuss its timeline and factors, mechanisms of resistance, control strategies, and conclusions. The presentation covered intrinsic and acquired resistance, genetic and biochemical mechanisms of resistance such as mutations, plasmids, conjugation, transduction, transformation, transposons, integrons, and production of antibiotic inactivating enzymes. It emphasized that antimicrobial resistance is a major global health concern.
Calprotectin (CP) is a metal-chelating protein produced by neutrophils during inflammation. CP inhibits the growth of Helicobacter pylori, a major risk factor for gastric cancer, by sequestering the metals manganese and zinc. Studies show that CP reduces the activity of H. pylori's cag Type IV Secretion System (T4SS) in a zinc-dependent manner by inhibiting T4SS pilus biogenesis. This decreases H. pylori's ability to translocate the oncoprotein CagA into gastric cells and reduce inflammation. While CP limits H. pylori growth and virulence, it also allows the bacteria to persist by modulating the inflammatory response.
Of 150 E. coli strains cultured from cattle in Europe, 3 were resistant to colistin. One strain was found to carry the mcr-1 gene, conferring plasmid-mediated colistin resistance. This strain also showed resistance to beta-lactams, florfenicol, and fluoroquinolones. Whole genome sequencing identified resistance genes and plasmids in the 3 colistin-resistant strains. The mcr-1 gene was found on a plasmid in one strain isolated in France in 2007, demonstrating the presence of this gene in livestock in Europe.
This document discusses biochemical tests used to identify and differentiate streptococci species. It describes characteristics of streptococci and how they can be classified based on hemolytic patterns on blood agar and Lancefield grouping. Key differentiation tests discussed include the bacitracin test to identify Streptococcus pyogenes, the CAMP test for S. agalactiae, optochin susceptibility and bile solubility for S. pneumoniae versus viridans streptococci, and inulin fermentation. Biochemical reactions and test results are summarized to differentiate between common streptococci.
Streptococcus is a genus of bacteria that includes several species that are pathogens. They are spherical, gram-positive cocci that can be α-hemolytic, β-hemolytic, or non-hemolytic. Important pathogenic species include Streptococcus pyogenes (group A streptococcus), a cause of pharyngitis and skin infections, and Streptococcus agalactiae (group B streptococcus), a cause of neonatal sepsis and meningitis. Enterococcus faecalis is a frequent cause of hospital-acquired infections like urinary tract infections. Viridans streptococci commonly cause infective endocarditis. Identification involves culturing samples and observing hemolysis and sensitivity to antibiotics like bac
Streptococcus pneumoniae, commonly known as pneumococcus, is a Gram-positive bacterium that is a major cause of pneumonia. It has over 90 known serotypes and uses an antiphagocytic polysaccharide capsule as a main virulence factor. Identification methods include culture characteristics such as being optochin positive and bile soluble as well as serological tests like the Quellung reaction.
teaching support for 2nd year medical school students: steps of the laboratory diagnosis of infections caused by bacteria of the genera Staphylococcus and Streptococcus
Este documento describe las características morfológicas, bioquímicas y de cultivo de cuatro especies de estreptococos: Streptococcus pyogenes, Streptococcus viridans, Enterococcus faecalis y Streptococcus pneumoniae. Detalla su morfología, estructura antigénica, aislamiento, características de cultivo, pruebas bioquímicas, susceptibilidad a antibióticos, epidemiología, patología y pruebas de diagnóstico.
Streptococcus pyogenes is a Gram positive coccus that forms chains and causes beta hemolysis on blood agar. It is classified by Lancefield grouping based on cell wall carbohydrates and Griffith typing based on M proteins. S. pyogenes causes respiratory, skin, and genital infections and can lead to post-streptococcal sequelae like rheumatic fever and glomerulonephritis. Penicillin is usually the treatment of choice.
Streptococcus pyogenes, also known as Group A Streptococcus, is a common human pathogen. It causes a variety of infections including pyogenic infections, pharyngitis, impetigo, erysipelas, necrotizing fasciitis, and can lead to post-infectious complications like rheumatic fever and glomerulonephritis. S. pyogenes is a Gram-positive coccus that grows in chains and produces several virulence factors like streptolysins and pyrogenic exotoxins that contribute to its pathogenicity. It is identified through culture, antigen detection, and serological tests. Treatment involves penicillin and prevention focuses on vaccination to reduce rheumatic fever
The document discusses molecular mechanisms of multi-drug resistance (MDR) in bacteria. It notes that in 2015, approximately 4,80,000 people worldwide developed MDR tuberculosis. Reasons for the rise of antimicrobial resistance include overuse of antibiotics, inappropriate prescribing, extensive agricultural use, few new antibiotics, and regulatory barriers. It defines MDR, XDR, and PDR resistance and describes the basic ways that bacteria acquire resistance, including decreasing intracellular drug concentration and modifying or inactivating drug targets. The document also summarizes recent understandings of resistance mechanisms such as reduced permeability through porins, increased drug efflux, mutations that modify drug targets, and enzymes that directly modify or inactivate antibiotics.
Conjugation, transposition and antibiotic resistanceAtika Noor
Bacteria can become resistant to antibiotics through several mechanisms, including modification of antibiotic molecules, modification of antibiotic targets, and alterations in bacterial genomes. Resistance genes can spread between bacteria through conjugative plasmids and transposons. Conjugative plasmids contain the machinery for transfer between bacterial cells through conjugation. Transposons are DNA segments that can move within genomes. Composite transposons contain resistance genes flanked by insertion sequences that allow the resistance genes to spread. Conjugative transposons not only transpose but also direct their own transfer between cells. Lateral gene transfer through these mobile genetic elements is a major cause of the rise and spread of antibiotic resistance in bacterial populations.
Study of alterations of bacterial membrane proteins involved in β lactam sens...Alexander Decker
The document summarizes a study on alterations in bacterial membrane proteins involved in β-lactam antibiotic sensitivity in Bacillus subtilis. Key findings include:
1) Ceftriaxone was more effective than cefazolin against Bacillus subtilis, with minimum inhibitory concentrations of 1.5 ppm and 18 ppm respectively.
2) Sensitivity to β-lactams was higher under acidic conditions versus alkaline conditions.
3) Growth was enhanced in the presence of the chelating agent EDTA along with β-lactam antibiotics, suggesting membrane proteins play a role in antibiotic sensitivity.
This document discusses objectives and research questions related to determining the minimum inhibitory concentration (MIC) values for various bacteria using antibiotic susceptibility testing. It aims to identify how disc susceptibility tests can be used in the antibiotic drug discovery process. It also provides background on bacterial cell anatomy, classifications of antibiotics by their mechanisms of action including targeting cell walls, protein biosynthesis, DNA replication, and folic acid metabolism. Mechanisms of antibiotic resistance for bacteria include reduced outer membrane permeability, efflux pumps, target molecule modification, and enzymatic inactivation or modification of antibiotics.
This document summarizes research on optimizing the use of aminoglycoside antibiotics. It finds that:
1) Bacterial killing by aminoglycosides correlates best with the area under the curve (AUC) ratio for most gram-negative infections, though peak concentration may be more important for Pseudomonas aeruginosa.
2) Larger, less frequent doses of aminoglycosides produce more rapid initial bacterial killing than smaller, more frequent doses of the same total amount.
3) Once-daily dosing of aminoglycosides has similar efficacy to multiple daily doses but is associated with lower risks of nephrotoxicity, especially if used for shorter courses of therapy up to 5-6 days
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
Antimicrobial resistance has developed as a serious threat due to overuse and misuse of antibiotics. Key bacterial infections like pneumonia, meningitis and tuberculosis are showing resistance to first-line drugs. This results in prolonged illness, higher mortality and increased healthcare costs to use second and third-line drugs. Resistance develops through genetic mutations and transfer of genes between bacteria. Improving antibiotic use can help control the emergence and spread of resistance.
The document provides an overview of medical microbiology and bacteriology. It discusses various gram-positive and gram-negative cocci and their associated diseases. It then reviews the sites of antibiotic action in bacteria, including inhibition of cell wall synthesis by beta-lactams, cell membrane disruption by polymyxins, DNA inhibition by quinolones and metronidazole, inhibition of transcription by actinomycin D and rifampin, and inhibition of translation in the bacterial ribosome by various antibiotics classes that bind to the 30S or 50S subunits. It also discusses competitive antagonistic antibiotics that inhibit metabolic pathways like isoniazid, sulfonamides, and trimethoprim.
Antibiotic-induced sepsis occurs when antibiotics cause an excessive release of endotoxins or exotoxins from bacteria, triggering an inflammatory response. Certain antibiotics that target bacterial cell wall synthesis, such as penicillins and cephalosporins, are more likely to cause endotoxin release. The choice of antibiotic class and dose is important in severely ill septic patients to avoid additional toxin release. Aminoglycosides inhibit bacterial protein synthesis with less endotoxin release and can be combined with beta-lactam antibiotics to treat severe sepsis and septic shock while minimizing endotoxin liberation.
Myself Gaurav Chaudhary, Assistant Professor, I.T.S. College of Pharmacy.
The Slideshare contains complete Notes of Unit-1 Medicinal Chemistry-III BP601T
It contains the Classification, stereochemistry chemical degradation, and Structure-activity relationship of Antibiotics(Penicillin, Cephalosporins, Monobactum, Aminoglycosides).
The study material is authentic.
Engineering of Phage-Derived Lytic Enzymes: Improving Their Potential as Antimicrobials
Carlos São-José
ID
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa,
Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; csaojose@ff.ul.pt; Tel.: +351-217-946-420
The document summarizes the mechanisms of drug resistance in Mycobacterium tuberculosis. It discusses the organism's innate impermeable cell wall and efflux pumps that help it withstand antibiotics. It also describes how mutations in specific genes can confer resistance to different drugs, such as mutations in rpoB conferring rifampin resistance, and katG or inhA mutations leading to isoniazid resistance. The slow metabolism of M. tuberculosis during dormancy also enhances its natural resistance by outlasting the effects of antibiotics. Understanding these molecular mechanisms of drug resistance is important for developing new drug targets to treat tuberculosis.
Drug delivery strategies for combating multiple drug resistancetanimittal
This document discusses strategies for combating multiple drug resistance. It begins with an overview of Darwin's theory of survival of the fittest applying to microbes developing resistance. It then discusses the historical background and definitions of drug and multiple drug resistance. It covers various types and mechanisms of developing resistance, including enzymatic, genetic and acquired resistance. It also discusses specific multidrug resistant organisms like MRSA, VRE and ESBLs. The document then covers various resistance mechanisms like efflux pumps, modified target sites and enzymatic degradation. It discusses applications to diseases like tuberculosis, urinary tract infections and the emergence of "superbugs". It concludes with the need for new strategies like nanotechnology to combat evolving drug resistance.
This document discusses the history and mechanisms of antimicrobial resistance. It begins with an overview and then discusses the history of antibiotic resistance, how it was first observed by Alexander Fleming. It explains intrinsic and acquired resistance in bacteria, how resistance can be transmitted between organisms, and various mechanisms of resistance including efflux pumps, enzymatic inactivation, and modification of drug targets. The document provides specific examples of resistance mechanisms for different classes of antibiotics in various bacterial species.
1) Lantibiotics are a class of antimicrobial peptides that contain thioether amino acids and dehydrated amino acids. They are ribosomally synthesized as precursor peptides and undergo post-translational modifications to become biologically active.
2) Lantibiotics act by binding to lipid II, which is involved in bacterial cell wall biosynthesis, inhibiting its function. This disrupts cell wall synthesis and can lead to pore formation.
3) Salivaricins are lantibiotics produced by Streptococcus salivarius that inhibit pathogenic oral bacteria and have potential as probiotics. They demonstrate activity against bacteria involved in dental caries, gingivitis, and oral malodor.
Mycoplasmas are the smallest and simplest self-replicating bacteria .These microorganisms lack a rigid cell wall and are bound by a single membrane, the plasma membrane. The lack of a cell wall is used to distinguish these microorganisms from ordinary bacteria and to include them in a separate class named Mollicutes. Most human and animal mollicutes are Mycoplasma and Ureaplasma species of the family Mycoplasmataceae. Because mycoplasmas have an extremely small genome, these organisms have limited metabolic options for replication and survival. The smallest genome of a self-replicating organism known at present is the genome of Mycoplasma genitalium (0.58 Mb). Owing to their limited biosynthetic capabilities, most mycoplasmas are parasites exhibiting strict host and tissue specificities. The mycoplasmas enter an appropriate host in which they multiply and survive for long periods of time. These microorganisms have evolved molecular mechanisms needed to deal with the host immune response and the transfer and colonization in a new host. These mechanisms include mimicry of host antigens, survival within phagocytic and nonphagocytic cells, and generation of phenotypic plasticity. The major question is whether mycoplasmas cause damage to the host cells and to what extent the damage is clinically apparent. Mycoplasmas have long resisted detailed analyses because of complex nutritional requirements, poor growth yields, and a paucity of useful genetic tools. Although questions still far outnumber answers, significant progress has been made in identifying the mechanisms by which mycoplasmas interact and damage eukaryotic host cells. Many animal mycoplasmas depend on adhesion to host tissues for colonization and infection. In these mycoplasmas adherence is the major virulence factor, and adherence-deficient mutants are avirulent. Primary interactions between the host and mycoplasma cells occur through cell surface adhesins produced by the mycoplasma. The adhesins have been characterized in only a limited number of mycoplasmas, and while there are homologs of the characterized adhesins in some other mycoplasmas, it is clear that different molecules and structures may be involved in adhesion in different species.
Similar to Mecanismos de resistencia del Streptococcus pneumoniae (20)
1) Streptococcus pneumoniae (pneumococcus) is a common cause of community-acquired pneumonia worldwide. It colonizes the upper respiratory tract of healthy individuals but can invade the lungs and cause disease.
2) The pneumococcus genome contains genes that allow it to both colonize the upper airways and cause invasive disease. Specific clones have developed phenotypes optimized for either colonization or invasion.
3) Risk factors for invasive pneumococcal disease include young or old age, medical conditions that impair the immune system like asplenia or HIV, and antecedent viral infections like influenza. Vaccines have reduced the incidence of disease caused by vaccine-targeted serotypes but non-vaccine serotypes
La Unión Europea ha acordado un embargo petrolero contra Rusia en respuesta a su invasión de Ucrania. El embargo prohibirá la mayoría de las importaciones de petróleo ruso a la UE a partir de finales de año. Se espera que el embargo aumente los precios mundiales del petróleo, pero los líderes de la UE creen que es necesario aumentar la presión económica sobre Rusia para poner fin a la guerra.
This document discusses the pathophysiology of diarrhea in children. It begins by describing normal intestinal function, including digestion, fluid and electrolyte transport, and the mechanisms that maintain equilibrium. Diarrhea occurs when there is increased intestinal secretion, reduced absorption, or a combination of both. Common causes of diarrhea in children include infectious diarrhea from bacteria or viruses, malabsorption from conditions like cystic fibrosis or coeliac disease, food allergies, and surgical resections of the intestine. Understanding the normal physiology and mechanisms of diarrhea allows clinicians to better diagnose and treat children with gastrointestinal issues.
Diarrea aguda infecciosa en pediatria, epidemiologia, prevencion y tratamientofranklinaranda
This document discusses acute diarrheal disease in children. It notes that diarrhea is a leading cause of morbidity and mortality in children worldwide, responsible for 2-3 million deaths per year. In the US, acute diarrhea accounts for 9% of pediatric hospitalizations. The causes of acute diarrhea vary but include viruses like rotavirus and norovirus, as well as bacterial and parasitic pathogens. Treatment focuses on fluid replacement and management, while prevention efforts include vaccination against rotavirus.
Bacterial diarrhea remains a major global health problem and common reason for patients seeking medical care. While strategies can improve diagnostic ability, such as increasing stool culture yield and new rapid tests, emerging antimicrobial resistance among common bacterial causes has challenged treatment. Recent studies showing favorable results for rifaximin, a nonabsorbed antibiotic, provide a potential solution as resistance grows to traditionally used antibiotics. However, prudent antibiotic use remains important to slow further development of resistance.
This document summarizes research on nontypeable Haemophilus influenzae (NTHi), an important cause of respiratory infections. It discusses how NTHi can exist as either a commensal or pathogen in the human respiratory tract. As a commensal, NTHi must dampen the host inflammatory response and evade defenses. As a pathogen, NTHi can adhere to and invade respiratory epithelial cells, initiating proinflammatory pathways. Different NTHi strains possess varying combinations of virulence factors like adhesins, and utilize phase variation to modulate host interactions. The host response ultimately determines the outcome of colonization.
Haemophilus influenzae is a small, gram-negative bacterium that colonizes the human respiratory tract. It requires factors X and V for growth that can be supplied by erythrocytes. There are encapsulated and nonencapsulated strains, with encapsulated type b strains historically causing most invasive infections in children. Nontypeable strains cause mainly mucosal infections like otitis media and exacerbations of chronic lung diseases. Immunity to H. influenzae is complex, with antibodies targeting strain-specific surface antigens, leaving hosts susceptible to recurrent infections by different strains. Effective conjugate vaccines against type b strains have greatly reduced invasive infections in children.
1. Streptococcus pneumoniae is a major cause of pneumonia, meningitis, and other infectious diseases. It was one of the first pathogens shown to be extracellular and cause disease through replication outside of cells.
2. Early studies in the late 19th/early 20th century established S. pneumoniae's role in causing pneumonia epidemics and demonstrated that immunization with killed pneumococci or antiserum could prevent disease.
3. S. pneumoniae has 91 known serotypes based on capsular polysaccharides and was important in establishing the concept of serotype-specific immunity and developing polysaccharide vaccines.
Streptococcus pneumoniae is an important bacterial pathogen that causes pneumonia, meningitis, and other infectious diseases. It played a central role in the early discoveries of humoral immunity and that DNA is the genetic material. There are over 90 serotypes of S. pneumoniae identified based on differences in their capsular polysaccharides. The bacterium has a cell wall containing peptidoglycan and teichoic acid, and an external capsule made of repeating oligosaccharides that are responsible for its serotype classification.
1. Streptococcus pneumoniae is a major cause of pneumonia, meningitis, and other infectious diseases. It was one of the first pathogens shown to behave as an extracellular pathogen and stimulate humoral immunity.
2. S. pneumoniae played a central role in early microbiology discoveries including the identification of DNA as the genetic material.
3. S. pneumoniae commonly colonizes the nasopharynx and can cause invasive disease. Rates of invasive disease vary by age and are higher in infants, young children, and older adults.
Solucion salina en diarrea aguda infecciosafranklinaranda
This randomized study compared the effects of isotonic saline (0.9% saline) versus hypotonic saline (0.45% saline) for intravenous rehydration of children with gastroenteritis. 102 children were randomized to receive either isotonic or hypotonic saline. Plasma electrolytes were measured before and 4 hours after starting IV fluids. Children receiving hypotonic saline showed no change in sodium levels if initially hyponatremic, but became hyponatremic if initially normal. In contrast, children receiving isotonic saline became less hyponatremic if initially low, and remained normal if baseline was normal. No child became hypernatremic with either fluid. Isotonic saline is preferable for preventing hyponatremia
Fluido isotonico en rehidratacion pediatricafranklinaranda
This study aimed to determine if using isotonic fluids instead of hypotonic fluids prevents iatrogenic hyponatremia in pediatric patients requiring intravenous fluid maintenance therapy. 122 pediatric patients were randomly assigned to receive either isotonic fluids with 140 mEq/L sodium or hypotonic fluids with <100 mEq/L sodium. At 24 hours, the percentage of patients with hyponatremia was significantly higher in the hypotonic group compared to the isotonic group. The use of isotonic fluids did not increase adverse events compared to hypotonic fluids. The study concludes that hypotonic fluids increase the risk of hyponatremia in pediatric patients.
Three children presented to a hospital emergency department with seizures caused by camphor poisoning. The children ranged from 15 to 36 months old. Two children ingested camphor, while one was exposed through repetitive skin rubbing. All three required medical intervention to stop the seizures. Further investigation revealed that illegally imported camphor products were being widely used in certain communities as remedies, despite known risks of toxicity in young children. Public warnings were issued about the dangers of unregulated camphor use.
This document provides a practice guideline for the out-of-hospital management of camphor poisoning based on an expert consensus process and review of current scientific literature. The guideline consists of 9 recommendations for triaging and managing patients with suspected camphor exposures, including when to refer patients to the emergency department based on symptoms and estimated ingestion amount. The objective is to help poison centers provide appropriate care and avoid unnecessary emergency visits while optimizing patient outcomes.
This document discusses the role of infections in different types of urticaria (hives). It summarizes that while infections are a clear trigger for acute spontaneous urticaria, their role in other urticaria subtypes is less clear. Treatment of infections like Helicobacter pylori has been shown to help resolve chronic urticaria in some cases. The document reviews evidence that viral and bacterial infections can trigger acute urticaria episodes, especially in children, and discusses the possible pathogenesis through mast cell activation. It aims to update understanding of how infections may contribute to different urticaria conditions.
This document discusses the role of infections in different types of urticaria (hives). It summarizes that while infections are a clear trigger for acute spontaneous urticaria, their role in other urticaria subtypes is less clear. Treatment of infections like Helicobacter pylori has been shown to help resolve chronic urticaria in some cases. The document reviews evidence that viral and bacterial infections can trigger acute urticaria episodes, especially in children, and discusses the possible pathogenesis through mast cell activation. It aims to update understanding of how infections may contribute to different urticaria conditions.
Rotavirus, infeccion local y sistemica, Fisiopatologiafranklinaranda
This document summarizes our current understanding of the pathogenesis of intestinal and systemic rotavirus infection. Rotaviruses primarily cause gastroenteritis in children under 5 years old. The diarrhea is thought to be caused by multiple factors, including malabsorption due to enterocyte destruction, a viral enterotoxin (NSP4), and stimulation of the enteric nervous system. Recent evidence suggests rotavirus infection disrupts calcium homeostasis in enterocytes through NSP4, increasing intracellular calcium levels and disrupting tight junctions. NSP4 may also directly induce chloride secretion from crypt cells or stimulate the enteric nervous system to induce secretion. While rotavirus infection is usually limited to the intestine, rare systemic infections have been reported.
Lavado de manos y mascarillas son utiles para efranklinaranda
This cluster randomized controlled trial investigated whether hand hygiene and facemasks can prevent household transmission of influenza. The study assigned 407 households in Hong Kong to control (lifestyle advice only), hand hygiene, or hand hygiene plus facemasks interventions. It found that hand hygiene and facemasks seemed to reduce influenza transmission in households, especially when started within 36 hours of symptoms in the infected household member, with an adjusted odds ratio of 0.33 for transmission among those using facemasks and hand hygiene. However, adherence to the interventions was low. The findings suggest that nonpharmaceutical interventions may help mitigate pandemic and seasonal influenza if implemented early.
1) A randomized controlled trial compared the effectiveness of surgical masks vs N95 respirators in preventing laboratory-confirmed influenza among 446 nurses during the 2008-2009 influenza season.
2) Laboratory-confirmed influenza occurred in 50 nurses (23.6%) in the surgical mask group and 48 nurses (22.9%) in the N95 respirator group, showing noninferiority of surgical masks.
3) Among nurses in Ontario tertiary hospitals, use of surgical masks resulted in similar rates of laboratory-confirmed influenza as N95 respirators.
2. based on the fact that they do not interact with PBP2b.
Pneumococci more resistant to the extended-spectrum
cephalosporins than to penicillin G have been described;
this pattern of resistance appears to be due to unique
alterations in PBPs such as PBP2x and PBP1a (table I) [7].
In pneumococcus, the genes that encode the altered
PBPs are called mosaic genes. This feature refers to the
existence of long, contiguous nucleotide sequences within
the PBP genes, which appear to be divergent, i.e. non-
pneumococcal origin [8]. Mosaic genes have emerged in
naturally transformable organisms like neisseriae and strep-
tococci most likely due to the ability to exchange genetic
material via homologous recombination of distinct alleles
[5]. The presence of extended DNA sequences in the PBP
genes modifies not only the active site of these proteins but
perhaps also some secondary domains involved in the
recognition of the muropeptide structure that these bacte-
ria use for building their particular clone-specific pepti-
doglycan [4, 9]. The origin of these mosaic blocks seems
to be traceable to other commensal species of strepto-
cocci, since closely related or even identical blocks of
sequences have been identified in resistant strains of Strep-
tococcus sanguis, Streptococcus mitis and Streptococcus
oralis [10–12]. The existence of identical PBP genes in
genetically distinct clones of penicillin-resistant S. pneu-
moniae demonstrates the horizontal spread of resistance
determinants within one species. A model for the origin of
penicillin resistance and the mechanism by which resis-
tance levels increase has been proposed [13, 14]. Acqui-
sition of mosaic genes may occur in a stepwise manner.
Incorporation of one of such altered low-affinity PBP gene
marks the beginning of a resistant clone, which then
expands through cell division until one of this lineage
engages in a second recombinational event that results in
the modification of another of the high-molecular-weight
PBP genes in the recipient pneumococcus. The progeny of
such a cell (which now has an increased MIC to penicillin)
may undergo further recombination events, each of which
increases the resistance level further [14].
Two alternative mechanisms of β-lactam resistance have
recently been described in vitro in pneumococcus. Both
mechanisms would most likely be involved in the biosyn-
thesis of cell wall components acting upstream of the
biosynthetic function of PBPs [4]. The first mechanism
involves a putative glycosyltransferase, CpoA, which
seems to act as the primary determinant. It was found in a
laboratory mutant obtained upon selection with piperacil-
lin, a highly lytic β-lactam that has high affinity to all
pneumococcal PBPs [15]. CpoA could be involved in
teichoic acid biosynthesis by transferring carbohydrates to
the lipid intermediate [4]. The second mechanism refers to
a putative histidine kinase encoded by the gene ciaH and
identified in a laboratory mutant resistant to cefotaxime, a
third generation cephalosporin that does not induce much
lysis [16]. It was proposed that the cia system might be
involved in sensing and counteracting cell wall damage
induced upon β-lactam treatment. No clinical correlate
implicating these alternative pathways of penicillin resis-
tance has been identified yet. No mechanism of penicillin
resistance involving β-lactamase has been reported thus
far in S. pneumoniae.
2.2. Fluoroquinolones
Quinolones such as the new fluoroquinolones, trova-
floxacin and moxifloxacin, appeared as alternative thera-
peutic agents for the treatment of penicillin-resistant pneu-
mococcal infections. Fluoroquinolones principally target
the type II topoisomerase A2B2 complex, also called DNA
gyrase, that catalyzes DNA supercoiling during replica-
tion, and the topoisomerase IV complex C2E2 that is essen-
tial for chromosome segregation [17].
In clinical isolates of pneumococci, fluoroquinolone
resistance is mediated by target modifications that involve
mutations in the gyrase genes, gyrA and gyrB, and in the
topoisomerase IV genes, parC and parE (table I). However,
in vitro studies have indicated that some strains may use
an efflux mechanism resulting in reduced intracellular
accumulation of the antibiotic [18, 19]. The presence of
mutations in gyrA and parC, the order of appearance of the
mutations and the type of fluoroquinolone that induce the
mutations constitute factors in the development of resis-
tance to fluoroquinolones. Ciprofloxacin resistance in
pneumococcus results from initial and necessary parC
mutations leading to low level of resistance, and subse-
quent gyrA mutations lead to higher levels of resistance
[20, 21]. The mutations in parC that have been described
thus far in clinical isolates and laboratory mutants involve
substitutions of Ser-79 to Tyr/Phe or Asp-83 to Gly/Ala, and
the mutations in gyrA include substitutions of Ser-83 to
Tyr/Phe or Glu-88 to Gln/Lys [20–23]. In contrast to cipro-
floxacin resistance, sparfloxacin resistance results initially
from mutations in gyrA and subsequently, additional muta
Table I. Mechanisms of antibiotic resistance in S. pneumoniae.
Antibiotic family Antibiotic agent Target Resistance mechanism
β-lactams penicillin PBPa
altered target
cephalosporin PBP altered target
Fluoroquinolones ciprofloxacin sparfloxacin DNA gyrase and topoisomerase IV altered target, efflux
DNA gyrase and topoisomerase IV altered target, efflux
Macrolides erythromycin 23S ribosomal RNA altered target, efflux
Chloramphenicol chloramphenicol 50S ribosomal subunit antibiotic enzymatic modification
Tetracycline tetracycline 30S ribosomal subunit altered target
Diaminopyrimidine trimethoprim DHFRa
altered target
Sulphonamide sulfamethoxazole DHPSa
altered target
a
PBP, penicillin-binding protein; DHFR, dihydrofolate reductase; DHPS, dihydropteroate reductase.
Review Charpentier and Tuomanen
1856 Microbes and Infection
2000, 1855-0
3. tions in parC. A mutation in gyrA resulting in substitution
of Ser-83 to Tyr/Phe and mutations in parC leading to
changes of Ser-79 to Tyr and Asp-83 to Asn were detected
in clinical isolates and laboratory mutants resistant to
sparfloxacin [23, 24]. High level of resistance to clina-
floxacin in laboratory mutants of S. pneumoniae requires
stepwise and multiple mutations in gyrA and parC [25]. By
aligning the DNA sequences of gyrA and parC, it is obvi-
ous that the mutation hotspots in gyrA (Ser-83 and Glu-88)
correspond to those in parC (Ser-79 and Asp-83). It was
thus proposed that the interactions of fluoroquinolones
with GyrA would be similar to those with ParC. The gyrB
and parE genes share significant homology. A mutation in
parE leading to a single amino acid substitution of Asp-435
to Asn was described in pneumococcal clinical and labo-
ratory mutants conferring low-level resistance to fluoro-
quinolone, whereas sequential acquisitions of mutations
in parE and gyrA are required to reach higher levels of
resistance [26, 27]. A mutation in gyrB changing Ser-127
to Leu that resulted in novobiocin resistance was reported
in laboratory mutants [22]. No mutation in gyrB conferring
quinolone resistance has yet been reported in pneumo-
coccal clinical isolates.
Antibiotic efflux was recently suggested to be a likely
relevant mechanism in clinical isolates of S. pneumoniae
resistant to fluoroquinolones (table I) [28, 29]. An active
efflux mechanism of fluoroquinolones similar to that con-
ferred by NorA, a membrane-associated active efflux pump
in Staphylococus aureus, was identified in a pneumococ-
cal laboratory mutant [30]. An efflux protein, PmrA, which
confers resistance to norfloxacin was recently character-
ized in vitro in S. pneumoniae [31].
2.3. Macrolide-lincosamide-streptogramins (MLS)
Although MLS antibiotics are chemically distinct, they
competitively interact when binding to the ribosomal 50S
subunit, where only one molecule is able to bind [32].
Two mechanisms of resistance to MLS in clinical iso-
lates of pneumococci have already been reported: modi-
fication of the target that results in co-resistance to MLS
and efflux of the antibiotic that mediates resistance to
14-membered and 15-membered macrolides only result-
ing in a so-called M phenotype (table I) [18, 33].
Co-resistance to MLS involves the gene erm encoding an
S-adenosylmethionine-dependent methylase that methy-
lates an adenine residue in the peptidyl transferase domain
of the 23S rRNA. The rRNA methylation leads most likely
to a conformational change in the ribosome, thus reducing
the affinity of MLS antibiotics for the rRNA [34]. Descrip-
tion of the gene ermAM carried on the conjugative trans-
poson Tn1545 or a transposon similar to Tn917 was
reported in pneumococcal clinical isolates [35]. The M
resistance phenotype is conferred by a mechanism of
efflux of the antibiotic from the cell [36]. The gene mefE
encodes a transmembrane hydrophobic protein that plays
a role of efflux pump by most likely using the proton
motive force. This mechanism appears to be rapidly emerg-
ing as the predominant mechanism of resistance to eryth-
romycin in clinical isolates of pneumococci isolated in
many countries [37].
2.4. Chloramphenicol
Chloramphenicol inhibits bacterial protein synthesis by
targeting the peptidyl transferase during translation [38].
In pneumococci, resistance to chloramphenicol is due
to the production of the chloramphenicol acetyltrans-
ferase enzyme catalyzing the conversion of chlorampheni-
col to derivatives, which are unable to bind the ribosomal
50S subunit and therefore are no longer capable of inac-
tivating the peptidyltransferase (table I) [39]. Pneumococ-
cal clinical isolates harboring the gene cat carried on the
conjugative transposon Tn5253, a composite transposon
consisting of the tetracycline resistance transposon Tn5251
and Tn5252 were identified [40]. Chloramphenicol-
resistant pneumococcal clinical strains containing
sequences homologous or identical to the cat gene
encoded by the plasmid pC194 from S. aureus have also
been reported [41, 42].
2.5. Tetracycline
Tetracyclines cause bacteriostasis by binding to either
the acceptor site (A-site) or the peptidyl-donor site (P-site)
of the 30S subunit of the bacterial ribosome, thus prevent-
ing binding of the aminoacyl-tRNA to the A-site [38].
Ribosomal protection mediated by the genes tet(M) and
tet(O) is the only resistance mechanism that has been
described thus far in pneumococcus (table I) [43, 44].
Pneumococcal resistant strains harboring tet(M) located
on the transposons Tn1545 and Tn5251 were isolated [40,
45]. The precise mechanism by which the proteins Tet(M)
and Tet(O) protect the ribosome from the action of tetra-
cycline is still unclear. It was suggested that Tet(M) would
promote the release of tetracycline from the ribosome in a
mechanism involving GTP as an energy source and that it
could function either as a tetracycline-resistant analog of
this elongation factor(s) or by modifying the target sites on
the ribosome in a catalytic fashion [46, 47]. It was also
considered that Tet(M) might be involved in modifying the
tRNA in such a way that its binding to the ribosome is not
affected by the presence of tetracycline [48].
2.6. Trimethoprim-sulfamethoxazole
The combination of trimethoprim with sulfamethox-
azole (cotrimoxazole) has been used extensively for the
treatment of lower respiratory tract infections in develop-
ing countries because of its attractive cost and effective-
ness [49]. Trimethoprim and sulfamethoxazole interfere
with the biosynthesis of folic acid [50]. Trimethoprim
selectively inhibits bacterial dihydrofolate reductase
(DHFR) thus preventing the reduction of dihydrofolate to
tetrahydrofolate. Sulfamethoxazole competes with para-
aminobenzoate for dihydropteroate synthetase (DHPS),
preventing the production of 7,8-dihydropteroate and thus
stopping DNA synthesis [50].
Trimethoprim resistance in clinical isolates of S. pneu-
moniae results from a single amino acid substitution (Ile-
100 to Leu) in the chromosomal-encoded DHFR (table I).
It was suggested that this amino acid change would prob-
ably disrupt the hydrogen bonding of the DHFR to the
4-amino group of trimethoprim thus altering the DHFR
function [51]. The nature of the mechanisms resulting in
high levels of trimethoprim resistance in pneumococcus
Antibiotic resistance and tolerance in S. pneumoniae Review
Microbes and Infection
2000, 1855-0
1857
4. remains unknown. Resistance to sulfamethoxazole in
pneumococcal clinical isolates is due to altered
chromosomal-encoded DHPS (table I) [49]. Duplication
of either three or six bases resulting in the repetition of one
or two amino acids in the region from Arg-58 to Tyr-63 of
the chromosomal-encoded DHPS was identified in a resis-
tant isolate. In a laboratory mutant, a duplication of amino
acids 66 and 67 in the chromosomal-encoded DHPS was
also described [52]. More recently, a duplication of Ser-
61, a duplication of Arg-58 and Pro-59 and an insertion of
an arginine residue between Gly-60 and Ser-61 in DHPS
were detected in South African clinical strains of S. pneu-
moniae resistant to trimethoprim-sulfamethoxazole [53].
2.7. Glycopeptides
The glycopeptide antibiotics, vancomycin and teico-
planin, exert their antimicrobial action by preventing both
the transglycosylation and transpeptidation reactions that
mediate the formation of mature cell wall [54]. They have
been considered as the drugs of last resort for infections
due to penicillin-resistant pneumococci. No resistance to
glycopeptides in S. pneumoniae has been thus far identi-
fied. Nevertheless, of great concern is the possibility that
the vancomycin-resistance genes found in enterococci
may be transferred to pneumococci. These enterococcal
genes encoding modified cell wall precursors with
decreased affinity for vancomycin could confer high levels
of resistance and are carried by transmissible elements
[55].
3. Epidemiology of antibiotic resistance
in S. pneumoniae
3.1. β-lactams
It was not until the 1960s that reports of strains of
pneumococci with intermediate levels of penicillin resis-
tance (MICs, 0.1–0.6 µg/mL) began to appear. The first
penicillin-resistant clinical isolate of S. pneumoniae (MIC,
0.5 µg/mL) was described in 1967 in Papua New Guinea
[1, 56].
Between 1967 and 1977, sporadic reports of penicillin-
resistant clinical isolates were published from various
parts of the world. The first dramatic report was the out-
break of epidemic pneumococcal disease caused by
multidrug-resistant strains in South Africa in 1977. In
addition to exhibiting greatly increased MICs of penicillin
of 4 to up to 8 µg/mL, these isolates were also resistant to
chloramphenicol or to tetracycline, erythromycin, clinda-
mycin and chloramphenicol [57, 58].
Since then, penicillin-resistant clinical isolates of pneu-
mococci have spread increasingly worldwide [2, 59]. By
the early 1980s, geographic areas where more than 10%
of isolates were found to be penicillin-resistant included
Israel, France, Hungary, Poland, Spain, South Africa, New
Guinea and the United States from New Mexico to Alaska.
During the 1980s in the United States, several large
multicenter studies showed that the prevalence of S. pneu-
moniae with decreased susceptibility to penicillin was
about 4–5% and bacteria with higher level resistance
(≥ 4 µg/mL) were extremely rare [60, 61]. During the same
period in a number of countries including South Korea,
Hungary and Spain, dramatic increases in penicillin resis-
tance were reported. In 1988 and 1989 in Hungary, an
epidemiological survey revealed that 58% of all pneumo-
coccal isolates and 70% of pneumococcal isolates from
children were resistant to penicillin [62]. In most parts of
the world where surveillance for resistant pneumococci
was performed at several time intervals, appearance of
isolates with low to intermediate resistance levels usually
preceded the appearance of more highly resistant bacte-
ria.
During the last decade, the areas with the highest
prevalence of penicillin-resistant pneumococci included
South Africa, Spain, France, eastern Europe, Israel, South
Korea, Japan, New Guinea and the most southerly areas of
South America [63, 64]. In the United States, the figure
changed abruptly with the proportion of penicillin-resistant
strains increasing to about 25% in certain geographic
locations [63, 65–68]. In some countries, like in Iceland,
penicillin- and multiply antibiotic-resistance emerged in
the 1990s, rapidly reaching frequencies close to 20% in
S. pneumoniae isolated from children [69]. Recent sur-
veillance studies in Latin America, eastern Europe and the
United States demonstrated evidence for similar importa-
tion of two distinct multiply antibiotic-resistant clones of
S. pneumoniae [70–72]. Although the mechanisms of resis-
tance are not directly linked, strains resistant to penicillin
are much more likely to be resistant to macrolides, tetra-
cycline, chloramphenicol and trimethoprim-sulfa-
methoxazole [59].
3.2. Fluoroquinolones
A surveillance study performed in Canada in 1988 and
between 1993 and 1998 on 7 551 isolates of S. pneumo-
niae revealed that reduced susceptibility to fluoroquino-
lones increased from 0% in 1993 to 1.7% in 1997 and
1998 and was associated with penicillin resistance [73]. In
Spain, among 2 822 pneumococcal strains isolated from
1991 to 1998, 2% were resistant to ciprofloxacin (MIC
≥ 4 µg/mL) with an increase from 0.9% in 1991–1992 to
3% in 1997–1998. A relation was observed between
ciprofloxacin resistance and penicillin resistance but also
with MLS resistance [74]. Of 1 037 clinical isolates exam-
ined from the United Kingdom, 273 showed reduced
susceptibility to norfloxacin or ciprofloxacin [28]. From a
recent study on 8 419 worldwide clinical isolates of
S. pneumoniae obtained during 1997–1998, 69 isolates
showed reduced susceptibility or resistance to fluoroqui-
nolones [23]. Recently, in Hong Kong, among 181 clinical
isolates of S. pneumoniae, 12.1% were found resistant to
ciprofloxacin (MIC > 2 µg/mL) [75].
3.3. MLS
Macrolide resistance has been frequently observed,
significantly limiting the usefulness of this class of drugs in
the treatment of pneumonia. S. pneumoniae resistant to
erythromycin was first observed in 1967 in Toronto [18].
In 1992 in France 27.5% of the pneumococcal strains
studied were resistant to erythromycin. Between 1991 and
1992 in the United States 3.7 and 2.2% of pneumococcal
Review Charpentier and Tuomanen
1858 Microbes and Infection
2000, 1855-0
5. strains isolated in children aged 1–2 years and 3–4 years,
respectively, were resistant to erythromycin [76]. Impor-
tantly, penicillin-resistant strains are frequently cross-
resistant to macrolides [77]. Since the first observation of
M resistance in pneumococci in Houston, Texas, the M
phenotype was shown to be present in as many as 85% of
erythromycin-resistant isolates in the United States [78]
and to be significantly increasing in clinical strains iso-
lated in South Africa [18]. In a recent study performed in
Taiwan, among 200 clinical isolates of S. pneumoniae
obtained from January 1996 to December 1997, a very
high rate of 82% were erythromycin resistant and 90%
clarithromycin resistant [79].
3.4. Tetracycline
Wide use of tetracyclines has resulted in resistance
developing in pneumococcal infections. The first pneu-
mococcal isolate resistant to tetracycline was isolated in
New South Wales in 1963 from a 10-month-old child with
pneumococcal meningitis [80]. Since then, reports on
tetracycline-resistant pneumococcal clinical isolates have
been described in the literature. As an example, among 91
pneumococcal strains isolated in children in Spain, 72.5%
were resistant to tetracycline [81].
3.5. Chloramphenicol
Chloramphenicol resistance in pneumococci was first
reported in 1970 in Poland, but since has not become a
major problem worldwide [18]. Although in Spain 30–50%
of clinical isolates of pneumococci have been reported to
be resistant to chloramphenicol, less than 5% of pneumo-
cocci isolated from other countries showed resistance
[82]. In developing countries, where the antibiotic is still
widely used, chloramphenicol resistance may be more
common.
3.6. Trimethoprim-sulfamethoxazole
The first clinical strain of pneumococcus resistant to
trimethoprim-sulfamethoxazole was first isolated in 1972
from a patient with an acute exacerbation of chronic
bronchitis [83]. The resistance impact in clinical isolates is
high, with the highest rate reported in Spain between 1984
and 1986, where the resistance rate among clinical iso-
lates was 67% [81]. More than 90% of co-trimoxazole-
resistant pneumococcal strains isolated in South Africa are
also resistant to penicillin and chloramphenicol [51]. Such
a high co-resistance to penicillin prevents the use of
co-trimoxazole for the treatment of penicillin-resistant
pneumococcal infections. In a recent study performed in
Taiwan, among 200 clinical isolates of S. pneumoniae
obtained from January 1996 to December 1997, a very
high rate of 87% were trimethoprim-sulfamethoxazole
resistant [79].
4. Mechanisms of antibiotic tolerance
and bacterial cell death
4.1. Autolytic enzymes
Cell wall hydrolases are required to maintain the pep-
tidoglycan during bacterial growth and split the septum
during cell separation. The expression of most hydrolases
is constitutive throughout the cell cycle, but the enzyme is
only active during stationary-phase lysis. To act as auto-
lysins, the hydrolases completely deregulate and entirely
degrade the cell wall [84]. Autolysis due to activation of
autolysins like the major autolysin LytA (an
N-acetylmuramoyl-L-alanine-amidase) is characteristic for
pneumococci.
In current models, the antibacterial effects of β-lactam
antibiotics are initiated by the binding of antibiotic to
PBPs. This binding inhibits specific steps in cell wall
synthesis, leading to the cessation of bacterial growth. The
bacteria then actively cooperate using their own enzy-
matic death machinery to achieve the final killing out-
come. Although fundamental to the action of penicillins,
the mechanism that explains how the inhibition of cell
wall synthesis or the binding of penicillins to PBPs acti-
vates autolysins remains unknown [85]. A secondary pro-
cess arising from the bacteria itself is necessary to trigger
these cell wall hydrolases to lead to cell death.
Antibiotic tolerance, a phenomenon distinct from anti-
biotic resistance, was first described in 1970 in pneumo-
cocci [86]. Antibiotic tolerance is best described by the
fact that antibiotic-binding to the bacterium becomes dis-
connected from the mechanism of killing. Antibiotic-
tolerant pneumococcal strains stop growing in the pres-
ence of conventional concentrations of antibiotics, but do
not go on to rapidly die. In most cases, antibiotic tolerance
goes with reduced lysis of the bacteria. Nevertheless, in
some instances, bacteria do not lyse upon binding to a
bactericidal antibiotic, but still undergo considerable cell
death [87]. Tolerance occurs due to two different settings:
phenotypic tolerance and genotypic tolerance.
4.2. Phenotypic tolerance
In response to deprivation of an essential nutrient, all
bacteria develop resistance to lysis by most β-lactam
antibiotics, a phenomenon termed phenotypic tolerance.
During this specific metabolic process, called the stringent
response, the bacterium shuts down the synthesis of mac-
romolecules such as DNA, phospholipids and cell wall
peptidoglycan [88]. One major characteristic of pheno-
typic tolerance had already been noted in the early 1940s,
where it became evident that non-growing bacteria are not
killed by penicillin. Since β-lactams bind normally to PBPs
of non-growing bacteria, the protection from the bacteri-
cidal antibiotic must arise by the control of activity of
autolytic enzymes, a process that is poorly understood.
This hypothesis is further substantiated by the fact that
autolysin preparations from non-growing strains retain
their hydrolytic activities when transferred to growing
cells. Phenotypic tolerance is not only restricted to depri-
vation of essential nutrients, non-growing or slow-growing
bacteria. It can also be induced by changes of the bacterial
environment, e.g., by lowering the pH of the medium or
by adding proteolytic enzymes or inhibitors of the autolytic
enzymes [89]. Similarly, addition of lipoteichoic acid
(Forssman antigen) to the growth medium of pneumococ-
cal cultures causes resistance to stationary-phase lysis and
penicillin tolerance, suggesting that lipoteichoic acids
might be involved in the in vivo control of autolysin
Antibiotic resistance and tolerance in S. pneumoniae Review
Microbes and Infection
2000, 1855-0
1859
6. activity. This assumption is supported by the observation
that lipoteichoic acids appeared to inhibit autolysin activ-
ity in several bacterial species [90–92].
4.3. Genotypic tolerance
In contrast to phenotypic tolerance (a response of all
bacteria to environmental changes), tolerance to antibiot-
ics can result from genetic mutations. Tolerance arises if
either the pneumococcal autolysin, which lyses the cell
wall, is not triggered or the autolysin itself is not active or
present. The most obvious example of tolerance is the
loss-of-function pneumococcal mutant in the autolysin
gene, lytA, which fails to lyse and dies very slowly [86].
However, no clinical isolates have been identified harbor-
ing a loss-of-function mutation of the autolysin gene.
Some studies suggest that 30% of clinical isolates of pneu-
mococci are genetically tolerant to penicillin [93]. There-
fore, clinical tolerance appears to arise by genetic alter-
ation at the level of regulation of autolysin activity [94].
In recent studies, loss-of-function pneumococcal
mutants were identified from a library of penicillin-tolerant
mutants. Analysis of the strains revealed several different
mechanisms interfering with the control of the pneumo-
coccal autolytic machinery: a two-component regulatory
system (VncS-R), ABC transporters (Psa and Pst), a zinc-
metalloprotease (ZmpB) and a heat-shock protein (ClpC)
[95–99].
4.4. Model for the control of bacterial cell death
One of the pneumococcal mutants from the library
failed to die in the presence of β-lactam antibiotics, includ-
ing vancomycin. The affected gene encoded a histidine
kinase, VncS, belonging to a two-component regulatory
system, VncS–VncR (figure 1) [97]. It was suggested that
the two-component system, VncS–VncR, represents an
early element in the autolytic trigger pathway, controlling
the activity of autolysin via levels of phosphorylation of
the response regulator VncR [97]. This implies that VncS–
VncR functions as a relay station reacting to cell density
signals (stationary-phase lysis) or the binding of antibiotics
to PBPs. Although there is still no evident link between cell
wall inhibition or PBPs and this system, a signal peptide
Pep27
has been identified, which might be a quorum-
sensing signal sensed by the two-component system,
VncS–VncR, necessary to trigger autolytic activity (figure
1) [100].
5. Conclusions and perspectives
The incidence of penicillin-resistant pneumococci has
increased dramatically worldwide, especially in the 1990s.
The spread of penicillin resistance appears to be due to a
global dissemination of several clones carrying both altered
PBP genes and genes encoding resistance to other antibi-
otic classes, including macrolides, tetracycline, chloram-
phenicol and trimethoprim-sulfamethoxazole. This situa-
tion is worsened by the recent emergence of high-level
resistance to extended-spectrum third generation cepha-
losporins [101]. The last-resort antibiotic for the treatment
of multidrug-resistant pneumococcal infections has
Figure 1. Model of autolysin triggering. Environmental signals regulate the addition of a phosphoryl group (P) to the sensor kinase
(VncS). This, in turn, controls whether the response regulator (VncR) is on (phosphorylated) or off (dephosphorylated). When VncR is
phosphorylated, genes that are turned on in response to antibiotics or stationary phase (and induce activation of autolysin, killing the
bacteria) are switched off. One of the trigger signals for bacterial lysis seems to be the peptide Pep27
, which acts in a quorum-sensing
manner. It is sensed by the two-component system, VncS–VncR, and determines with that the dephosphorylation of VncR, leading to cell
death. It remains to be established how and where inhibition of cell wall synthesis by antibiotics feeds into the death peptide pathway.
Review Charpentier and Tuomanen
1860 Microbes and Infection
2000, 1855-0
7. become the glycopeptide vancomycin [102]. The rapid
emergence of enterococcal strains harboring the
vancomycin-resistance gene complex in a highly transfer-
able form raises great concern of a likely transfer of van-
comycin resistance to multidrug-resistant pneumococci.
In addition to a more restricted application of antibiotics,
there is an urgent need for new antimicrobial agents that
are able to overcome the developed antibiotic-resistance
mechanisms.
S. pneumoniae is an autolytic pathogen, which regu-
lates its suicidal enzymatic system. The downregulation of
autolysis leads to tolerance and is of clinical significance
as underscored by reports that failure to eradicate tolerant
bacteria might result in prolongation and even failure of
therapy. Whether this has a broader impact on the general
clinical situation still has to be determined, but it seems
that in body sites of poor defense like the cerebrospinal
fluid compartment, antibiotic-tolerant bacteria might be
responsible for relapsing infections and treatment failures
[103, 104]. A signal transduction pathway involved in
controlling pneumococcal killing was recently uncov-
ered. Understanding of the function and regulation of all
bacterial suicidal participants is critical for the develop-
ment of new antibacterial agents which will not fail in
situations of difficult growth conditions.
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