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
Mechanism Antibiotic Resistance
Intrinsic (Natural)
Acquired
Chromosomal
Extra chromosomal
Intrinsic Resistance
Lack target : No cell wall; innately resistant to penicillin
2. Drug inactivation: Cephalosporinase in Klebsiella
3. Innate efflux pumps:
It is an active transport mechanism. It requires ATP.
Eg. E. coli, P. aeruginosa
Altered target sites
PBP alteration
Ribosomal target alteration
Decreased affinity by target modification
Beta-lactamase
Beta-lactamases are enzymes produced by bacteria that provide resistance to β-lactam antibiotics such as penicillins, cephamycins, and carbapenems
Major resistant Pathogen
1. PRSP- Penicillin resistant Streptococcus pneumoniae2. MRSA/ORSA- Methicillin-resistant Staphylococcus Aureus (Super bug)3. VRE -Vancomycin-Resistant Enterococci4. Carbapenem resistant pseudomonas aeruginosa5. Carbapenem resistant Carbapenem resistant 6. Extended spectrum beta-lactamase (ESBL)-producing bacteria
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
Mechanism Antibiotic Resistance
Intrinsic (Natural)
Acquired
Chromosomal
Extra chromosomal
Intrinsic Resistance
Lack target : No cell wall; innately resistant to penicillin
2. Drug inactivation: Cephalosporinase in Klebsiella
3. Innate efflux pumps:
It is an active transport mechanism. It requires ATP.
Eg. E. coli, P. aeruginosa
Altered target sites
PBP alteration
Ribosomal target alteration
Decreased affinity by target modification
Beta-lactamase
Beta-lactamases are enzymes produced by bacteria that provide resistance to β-lactam antibiotics such as penicillins, cephamycins, and carbapenems
Major resistant Pathogen
1. PRSP- Penicillin resistant Streptococcus pneumoniae2. MRSA/ORSA- Methicillin-resistant Staphylococcus Aureus (Super bug)3. VRE -Vancomycin-Resistant Enterococci4. Carbapenem resistant pseudomonas aeruginosa5. Carbapenem resistant Carbapenem resistant 6. Extended spectrum beta-lactamase (ESBL)-producing bacteria
Dr. Sachin Verma is a young, diligent and dynamic physician. He did his graduation from IGMC Shimla and MD in Internal Medicine from GSVM Medical College Kanpur. Then he did his Fellowship in Intensive Care Medicine (FICM) from Apollo Hospital Delhi. He has done fellowship in infectious diseases by Infectious Disease Society of America (IDSA). He has also done FCCS course and is certified Advance Cardiac Life support (ACLS) and Basic Life Support (BLS) provider by American Heart Association. He has also done a course in Cardiology by American College of Cardiology and a course in Diabetology by International Diabetes Centre. He specializes in the management of Infections, Multiorgan Dysfunctions and Critically ill patients and has many publications and presentations in various national conferences under his belt. He is currently working in NABH Approved Ivy super-specialty Hospital Mohali as Consultant Intensivists and Physician.
Introduction to bacterial resistance to antibiotics, types of resistance, brief explaining & examples
The lecture was presented at Al-Mahmoudiya General Hospital at Wed, 17th Nov. 2021
Represented & updated as part of the training course for fresh appointed pharmacist at 16/5/2023
Antibiotics Resistance is a new issue in Microbiology-Medicine aspects, taken from Lange Review of Medical Microbiology, this purpose is for education only
Antibiotic resistance,introduction, cause, mechanism and solution of Antibiot...Dr. Sharad Chand
A illustrative representation of the antibiotic resistance, its introduction, cause, mechanism, examples and possible solutions of the antibiotic resistance. with pictorial illustrations for better understanding.
beta lactamases : structure , classification and investigationsDr Taoufik Djerboua
this is a simple introduction to the world of beta lactamase enzymes that i had the chance to present during my observership in turkey. it bears some introductive notions necessary to the unverstading of the function fo these enzymes and some tests usually used to invistigate bacteria producing these enzymes. the pictures were taken from Microbe-edu.com Bush et al classification of Beta lactamase, the EUCAST and CLSI recommandation for susceptibility testing documents.
Anti-microbial resistance has become a world health issue today. Therefore it is imperative to know about the methods of acquiring resistance and ways to deal with the situation and prevent resistance.
Dr. Sachin Verma is a young, diligent and dynamic physician. He did his graduation from IGMC Shimla and MD in Internal Medicine from GSVM Medical College Kanpur. Then he did his Fellowship in Intensive Care Medicine (FICM) from Apollo Hospital Delhi. He has done fellowship in infectious diseases by Infectious Disease Society of America (IDSA). He has also done FCCS course and is certified Advance Cardiac Life support (ACLS) and Basic Life Support (BLS) provider by American Heart Association. He has also done a course in Cardiology by American College of Cardiology and a course in Diabetology by International Diabetes Centre. He specializes in the management of Infections, Multiorgan Dysfunctions and Critically ill patients and has many publications and presentations in various national conferences under his belt. He is currently working in NABH Approved Ivy super-specialty Hospital Mohali as Consultant Intensivists and Physician.
Introduction to bacterial resistance to antibiotics, types of resistance, brief explaining & examples
The lecture was presented at Al-Mahmoudiya General Hospital at Wed, 17th Nov. 2021
Represented & updated as part of the training course for fresh appointed pharmacist at 16/5/2023
Antibiotics Resistance is a new issue in Microbiology-Medicine aspects, taken from Lange Review of Medical Microbiology, this purpose is for education only
Antibiotic resistance,introduction, cause, mechanism and solution of Antibiot...Dr. Sharad Chand
A illustrative representation of the antibiotic resistance, its introduction, cause, mechanism, examples and possible solutions of the antibiotic resistance. with pictorial illustrations for better understanding.
beta lactamases : structure , classification and investigationsDr Taoufik Djerboua
this is a simple introduction to the world of beta lactamase enzymes that i had the chance to present during my observership in turkey. it bears some introductive notions necessary to the unverstading of the function fo these enzymes and some tests usually used to invistigate bacteria producing these enzymes. the pictures were taken from Microbe-edu.com Bush et al classification of Beta lactamase, the EUCAST and CLSI recommandation for susceptibility testing documents.
Anti-microbial resistance has become a world health issue today. Therefore it is imperative to know about the methods of acquiring resistance and ways to deal with the situation and prevent resistance.
Relative or complete lack of effect of antimicrobial agent against a previously susceptible microbe/pathogen.
It is an evolutionary principal that organism adopt genetically to change in their environment.
since the doubling time of bacteria can be as short as 20 mnt, there may be many generations in even a few hours, providing ample opportunity for evolutionary adaptation.
The phenomenon of resistance imposes serious constraints on the options available for the treatment of many bacterial infections.
The resistance to chemotherapeutic agents can also develop in protozoa, in multicellular parasites and in population of malignant cells.
Today there are different strains of S. aureus resistant to almost every form of antibiotic in use.
To understand the mechanisms of antimicrobial action and the classification of antimicrobial drugs.
To explain the process of microbial resistance.
To understand the spread of resistant microbes.
Outlines the prevention of microbial resistance.
Antibiotic resistance A major source of morbidity and mortality worldwide.pptxSmitha Vijayan
Antibiotic resistance is a naturally occurring process.
However, increases in antibiotic resistance are driven by a combination of germs exposed to antibiotics, and the spread of those germs and their resistance mechanisms
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
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This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
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Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
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Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
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2 Case Reports of Gastric Ultrasound
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
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New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
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Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
3. Agenda
I. Overview.
II. Origin of resistance
III. Major mechanisms of resistance
IV. Factors that promote bacterial resistance
V. Antibacterial in food and animal industries
VI. Consequence of antibiotics resistance
VII.New trends for overcoming bacterial resistance
VIII.Questions
4. overview
Worldwide, antibacterial resistance has increased dramatically over the
past few years and is currently recognized as a major medical challenge
in most healthcare settings.
After the discovery of penicillin in 1928, a number of treatment failures
and occurrence of some bacteria such as staphylococci which were no
longer sensitive to penicillin started being noticed. This marked the
beginning of the error of antimicrobial resistance.
Increasing prevalence of resistance has been reported in many
pathogens over the years in different regions of the world including
developing countries(Byarugaba, 2005). As MRSA, Pseudomonas
aeruginosa.
5. Overview
Throughout history, there has been a continual battle between
humans and the multitude of microorganisms that cause infection and
disease.
Examples:
Bubonic plague, tuberculosis, malaria, and more recently, the human
immunodeficiency virus/acquired immunodeficiency syndrome
pandemic, have affected substantial portions of the human population,
causing significant morbidity and mortality.
6. Definitions
Antimicrobial resistance (AMR):
• It’s define as resistance of a microorganism to an antimicrobial
medicine to which it was originally sensitive.
• Resistant organisms (they include bacteria, fungi, viruses and some
parasites) are able to withstand attack by antimicrobial medicines,
such as antibiotics, antifungals, antivirals, and antimalarial
•sothat standard treatments become ineffective and infections
persist increasing risk of spread to others. The evolution of
resistant strains is a natural phenomenon that happens when
microorganisms are exposed to antimicrobial drugs, and resistant
traits can be exchanged between certain types of bacteria.(WHO
2013)
7. (cont.)
Multi-drug resistance (MDR)
• Is defined as having acquired non-susceptibility to at least one
agent in three or more antimicrobial categories.
Extensive drug resistance (EDR)
• Is defined as non-susceptibility to at least one agent in all but
two or fewer antimicrobial categories (i.e. bacterial isolates
remain susceptible to only one or two categories).
Pandrug-resistant (PDR)
• Is defined as non-susceptibility to all agents in all antimicrobial
categories.
8. ORIGIN OF RESISTANCE
Bacterial resistance to antimicrobial agents may be
intrinsic or acquired, intrinsic resistance as resistance
of Mycoplasma species to B-lactams antibiotic, due to
it’s lack of cell wall and pleomorphic characters.
And acquired resistance is arise from de novo
mutation of DNA sequence or by horizontal gene
transfer by different mechanisms (transformation,
transduction and conjugation ).
9. Origin of resistance
Intrinsic resistance(IR)
is that type of resistance which is naturally coded and
expressed by all (or almost all) strains of that particular
bacterial species. An example of intrinsic resistance is the
natural resistance of anaerobes to aminoglycosides and Gram-
negative bacteria against Vancomycin.
the resistant genes are maintained in nature because of the
presence of antibiotics producing bacteria in soil. These
antibiotics act on other bacterial species other than the
producer bacteria, There has to be a mechanism of protection
in the host bacteria against the antibiotics that it produces,
which could be the source of genes encoding resistance
10. (cont.)
is the innate ability of a bacterial species to resist activity of a
particular antimicrobial agent through its inherent structural or
functional characteristics, which allow tolerance of a particular drug
or antimicrobial class. This can also be called “insensitivity” since it
occurs in organisms that have never been susceptible to that
particular drug. Such natural insensitivity can be due to:
I. lack of affinity of the drug for the bacterial target.
II. Inaccessibility of the drug into the bacterial cell.
III. Extrusion of the drug by chromosomally encoded active
exporters.
IV. Innate production of enzymes that inactivate the drug.
11. MECHANISMNATURAL RESISTANCE
AGAINST
ORGANISM
Lack of oxidative metabolism
to drive uptake of
aminoglycosides
AminoglycosideAnaerobic bacteria
Inability to reduce drug to
active form
MetronidazoleAerobic bacteria
Lack of PBPsAztreonamGram-positive bacteria
Lack of uptake(increase
thickness of PG layer)
VancomycinGram-negative bacteria
Beta-lactamaseAmpicillinKlebsiella spp.
Beta-lactamaseImipenemStenotrophomonas.
maltophila
Lack of appropriate cell wall
precursor target
VancomycinLactobacilli and Leuconostoc
Lack of uptake resultingSulfonamides, trimethoprim,
tetracycline, or
chloramphenicol
Pseudomonas aeruginosa
Lack of sufficient oxidative
metabolism to drive uptake of
aminoglycosides
AminoglycosidesEnterococci
Lack of PBPsAll cephalosporins
12. (cont.)
Acquired resistance(AR)
Acquired resistance is said to occur when a particular microorganism
obtains the ability to resist the activity of a particular antimicrobial
agent to which it was previously susceptible.
By mutation
By horizontal gene transfer
1. Mutation
It’s define as permanent change in the sequence of DNA nucleotide of
gene. This change can take place either by alteration, loss or gain of
the nucleotide.
Types
1. Spontaneous mutation ( occurs by natural physical agents as HEAT and
IRRADIATION , in which energize DNA nucleotide so that subsequent
intra-molecular rearrangement of bases lead to incorrect base –pairing
and ultimately mutation.
2. Induced mutation(occurs by intentional treatment of the cell with
physical or chemical agents that alter base sequences.
13. (cont.)
Other types of mutation:
1. Point mutation → change in single base-pair in the DNA.
2. Substitution → replacement of an original base-pair or sequence of
base-pair by another, may be transition (same) or transversion
(different).
3. Deletion.
4. Insertion.
5. Silent.
6. Reading frame shift mutation.
7. Non-sense.
8. Missense.
9. Lethal mutation.
10. Back mutation.
11. Condition lethal mutation.
12. Suppressor mutation.
14.
15. (cont.)
2- Horizontal gene transfer(HGT)
It’s recombination between two genetically different DNA
molecules, then the resistance is acquired. Acquisition of foreign
genetic elements in prokaryotes may occur by three main
mechanisms.
I. TRANSFORMATION → direct passage of free DNA (naked) from one
cell to another. The receiving bacteria then simply introduce the free
DNA in to their cytoplasm and then incorporate it to their own DNA.
II. TRANSDUCTION → transfer of genetic element by mean of vector
(usually virus) called bacteriophage.
III. CONJUGATION→it’s the most important and most common
mechanism of gen transfer, this mechanism is mediated by plasmid
(bacteria containing plasmid called F positive. But the other cell is
called F negative.
16. (cont.)
Transposon
It’s a mobile genetic element involved in horizontal gen transfer.
Have the ability to move from place to place on the chromosome and in to and out plasmid.
Types:
1- Replicative → it's leave a copy of itself at the original site.
2- Non replicative → it's not leave a copy of itself at the original site.
N.B. transposon can enter the functional gene
Size about 5 kilobases.
Two enzyme are involved in transposition process
1-Transposase
2-Resolvase
Transposon contains two inverted repeat, in which the two enzymes are identifying.
Mobile genetic element are probably responsible for most of the genetic variability in natural
bacterial population, and the spread of bacterial resistance genes.
Some transposons may contain a special, more complex DNA fragment called ‘‘integron’’, a site
capable of integrating different antibiotic resistance genes and thus able to confer multiple
antibiotic resistance to a bacteria. Integrons have been identified in both gram-negative and
gram-positive bacteria, and they seem to confer high-level multiple drug resistance to the
bacteria that carry and express them
17.
18.
19.
20.
21. MECHANISM INVOLVEDRESISTANCE OBSERVEDACQUIRED RESISTANCE
THROUGH
Point mutations in the
rifampin-binding region of
rpoB
Mycobacterium tuberculosis
resistance to rifamycins
Mutations
Mutations in the
chromosomal gene specifying
dihydrofolate reductase
E.coli, Hemophilius influenzae
resistance to trimethoprim
Via acquisition of mecA genes
which is on a mobile genetic
element called “staphylococcal
cassette chromosome”
(SCCmec) which codes for
penicllin binding proteins
(PBPs) that are not sensitive to
ß-lactam inhibition
Staphylococcus aureus
resistance to methicillin
(MRSA)
Horizontal gene transfer
22. Major biological mechanisms of antimicrobial
resistance
Whichever way a gene is transferred to a bacterium, the development of
antibiotic resistance occurs when the gene is able to express itself and produce a
tangible biological effect resulting in the loss of activity of the antibiotic.
Microbes utilize numerous mechanisms of resistance to antimicrobial
Drugs they can be summarized as follow:
I. Decreased uptake and increased efflux of drug from the microbial
cell.
II. Expression of resistance genes that code for an altered version of the
substrate to which the antimicrobial agent binds.
III. Covalent modification of the antimicrobial drug molecule which
inactivates its antimicrobial activity.
IV. Increased production of a competitive inhibitor of antibiotic.
V. Drug tolerance of metabolically inactive persisters.
VI. Biofilms.
VII. Swarming.
23. (cont.)
I. Decreased uptake(impermeability) and
increased efflux of drug from the microbial cell.
• Decreased uptake of antimicrobial drugs and/or use of transmembrane
efflux pumps prevents the concentration of antimicrobial agent from
increasing to toxic levels within the microbial cell (↓uptake↓conc↓effect).
• Gram negative bacteria have an outer membrane surrounding a periplasmic
space (which contains a peptidoglycan cell wall),which surrounds an
innermembrane, whereas Gram positive bacteria have a peptidoglycan cell
wall surrounding only a single plasma membrane.
• This outer membrane may provide an extra barrier against
drug uptake (especially hydrophobic drugs) in Gram
negative bacteria, which is not present in Gram positive
bacteria. This is one explanation why Gram negative
bacteria are less susceptible than Gram positive bacteria to
many antibiotics, including beta-lactams and macrolides.
24. (cont.)
• E.g. P. aeruginosa and E.coli are containing proton-dependant
efflux pump which expel the drug outside the cell.
• Exampls
Tetracyclin resistance byTetA,B and k gen mediated efflux pump.
Fluroquinolon resistance by decreas uptak
Vancomycin resistance By increas thickness of bacterial cell wall,
so decreas uptak.
EFFLUX
AND
IMMPERMEABILITY
25. (cont.)
II. Expression of resistance genes that code for an altered
version of the substrate to which the antimicrobial agent
binds
GENE mutation → translated to altered protein( substrate) → low binding
affinity→ reduced antibacterial activity → resistance developed.
E.g.
• MacA resistance gene codding for PBP2A (altered form
than wild-type), represent resistance of MRSA against B-
lactams.
• VanA resistance gene codding for altered binding
substrate (D-alanine–D-lactate ligase, Vancomycin has
1000 times lower affinity for D-alanine–D-lactate than D-
alanine–D-alanine, so the VanA gene confers resistance
to vancomycin. Both vancomycin resistant Enterococcus
(VRE) and vancomycin-resistant S. aureus (VRSA) express
VanA.
26. (cont.)
• Expression of altered DIHYDROFOLATE PETROATE represent sulfonamide
resistance, Bacteria using this resistance mechanism include S.
pneumoniae, S. pyogenes, Neisseria meningitidis, and E. coli.
• Altered gyrA and gyrB, represent resistance of Gm-ve against Quinolones.
• Altered Topoisomerase IV, represent resistance of Gm+ve against
Quinolones.
27. (cont.)
III. Covalent modification of the antimicrobial drug
molecule which inactivates its antimicrobial activity.
Microbes can also express drug resistance genes that code for
enzymes that covalently modify the antimicrobial drug, thereby
reducing its antimicrobial activity.
E.g.
i. beta-lactamases hydrolyze the beta-ring of betalactams,
thereby inactivating the antibiotic activity of the beta-
lactam molecule and conferring beta-lactam resistance.
ii. ACT N-acetyltransferse, which acetylates an NH2 group of
the aminoglycoside molecule.
iii. APH O-phosphotransferase, which phosphorylatesan OH
group of the aminoglycoside molecule.
iv. and the ANT O-adenyltransferase, which adenylates an OH
group of the aminoglycoside molecule.
v. Acetyltransferases, which acetylate and thereby inactivate
chloramphenicol.
28.
29. (cont.)
IV. Increase production of competitive inhibitors.
Bacteria can also achieve antibiotic resistance by
synthesizing a molecule that is a competitive inhibitor
of the antibiotic(Enzyme Substrate).
Example
Mechanism of sulfonamide resistance is increased
synthesis by bacteria of para-aminobenzoic acid
(PABA), which competes with the sulfonamide drug
for the binding site of bacterial dihydropteroate
synthetase.
This mechanism of sulfonamide resistance is used by S.
aureus and N. meningitidis.
30. (cont.)
V. Drug tolerance of metabolically inactive persisters.
The presence of metabolically inactive persisters at the site
of infection in close to actively bacterial population, results
in antibacterial tolerance.
Recurrence of infection after treatment is usually occur.
This mechanism occur due to expression of gene called
Toxin-Antitoxin, which cause their metabolic activity to
slow or stop.
After the hos exposed to antibacterial agent, the actively
metabolic bacterial of population eradicated.
And the persisters are turn to metabolically active and
cause recurrence of infection.
31. (cont.)
VI. Biofilm.
Biofilm formation can result in tolerance of bacteria to very high
concentrations of multiple antibiotics, resulting in chronic
infections despite antibiotic treatment.
Steps of biofilm
I. Formation of conditioning biofilm.
II. initial attachment.
III. Irreversible attachment and synthesis and secretion of a matrix
consisting of extracellular polymeric substance (EPS). This EPS
matrix accumulates and eventually surrounds the population
of bacterial cells
IV. Biofilm growing.
V. Detachment.
VI. Formation of a new conditioning biofilm in other site in host.
33. Role of Extracellular polymeric substance in resistanse
I. Act as barrier to diffusion of oxygen and nutrients. In turn the
deeply located bacteria to metabolically in active and tolerate
antibacterial agent rather than superficially located bacteria.
I. Decrease diffusion of antibacterial agent to bacterial population,
so concentration not reach to MIC due to:
Small pores of EPS.
The negative charge of the EPS matrix also traps antibiotic
molecules before they can affect the bacterial cells
Third, enzymes within the EPS matrix also covalently modify
antibiotic molecules, thereby inactivating their antimicrobial
activity.
34. (cont.)
VII.Swarming.
type of multicellularity in bacteria and operates by the
following mechanism:
I. Planktonic bacterial cells differentiate into elongated
cells with multiple flagella (swarm cell).
II. More swarm cell adhere together and act as single unit.
These swarm cells are also tolerant to antimicrobial
agent.
III. Subculturing of swarm cell in a liquid media, reverse
back to planktonic bacteria which no longer have
tolerance to antibacterial agent.
E.g. Bacillus subtilis, Serratia marcescens, E. coli, Salmonella
typhimurium and P. aeruginosa.
Planktonic form: are single-cells that may float or swim in a liquid
medium.
35. Factors that promote bacterial resistance
suboptimal use of antimicrobials for prophylaxis and
treatment of infection.
noncompliance with infection-control practices.
prolonged hospitalization, increased number and duration of
intensive care-unit stays, multiple comorbidities in
hospitalized patient.
increased use of invasive devices and catheters.
ineffective infection-control practices, transfer of colonized
patients from hospital to hospital
grouping of colonized patients in long-term-care facilities.
antibiotic use in agriculture and household chores.
increasing national and international travel.
Lack of education and poverty.
37. Antibacterial in food and animal industries
Veterinary antibiotics (VAs) are widely used in many countries worldwide to treat disease
and protect the health of animals.
They are also incorporated into animal feed to improve growth rate and feed efficiency.
As antibiotics are poorly adsorbed in the gut of the animals, is excreted unchanged in faeces
and urine. Given that land application of animal waste as a supplement to fertilizer.
there is a growing international concern about the potential impact of antibiotic residues on
the environment.
E.g. tetracycline, chloramphenicol, triclosan and bacitracin.
38.
39. New trends for overcoming bacterial resistance
Due to global emergence of antibacterial resistance,
scientists are introduce a new strategies to overcome
resistance.
Many of this strategies are
I. Plant compounds with resistance modifying activities.
II. Nanotechnology as a therapeutic tool to combat microbial
resistance.
40. I. Some antibiotic resistance modifying compounds from plants
REFERANCEANTIBIOTIC
POTENTIATED
PLANT SOURCECOMPOUND
Smith et al. (2007)Oxacillin, Tetracycline,
Norfloxacin
Tetracycline
Chamaecyparis
lawsoniana
Ferruginol
5-Epipisiferol
Marquez et al. (2005)Ciprofloxacin,
Norfloxacin,
Pefloxacin, Acriflavine
and Ethidium bromide
Jatropha elliptica2,6-dimethyl-4-
phenylpyridine-
3,5-dicarboxylic
acid diethyl ester
Oluwatuyi et al.
(2004)
ErythromycinRosmarinus officinalisCarnosic acid carnosol
Shibata et al. (2005)B-lactamsCaesalpinia spinosaEthyl gallate
Gibbons et al. (2004)
Hu et al. (2002)
Zhao et al. (2001)
Norfloxacin
Imipenem
Panipenem
B-Lactams
Camellia sinensisEpicatechin gallate
Epigallocatechin
gallate
41. II. Nanotechnology as a therapeutic tool to combat
microbial resistance.
Use of nanoparticles is among the most promising
strategies to overcome microbial drug resistance.
Example
Nanoparticles with multiple simultaneous mechanisms of action
against microbes
Nitric oxide-releasing nanoparticles (NO NPs).
Chitosan-containing nanoparticles (chitosan NPs).
Metal-containing nanoparticles.
Nanoparticles that target antimicrobial agents to the
site of infection.
Liposomes nano-particles.
Dendrimers.