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Antimicrobial resistance mechanism


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for MD pharmacology

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Antimicrobial resistance mechanism

  2. 2. CONTENTS :- • Introduction • Natural Resistance • Acquired Resistance • Resistance Mechanisms - Biochemical - Mutation - Gene Transfer • Cross Resistance • Prevention of Drug Resistance
  3. 3. INTRODUCTION :- • WHO - Defines as micro-organisms that are not inhibited by usually achievable systemic concentration of an antimicrobial agent(AMA) with normal dosage schedule and / or fall in the minimum inhibitory concentration (MIC) range. • when a species is subjected to chemical warfare, that threatens its extinction it often evolves mechanisms to survive under that stress development of resistance.
  4. 4. • Two major factors are associated with emergence of antibiotic resistance: - Evolution - Clinical/ Environmental practices.
  5. 5. NATURAL RESISTANCE :- • Some microbes lack the metabolic process or the target site for particular drug. • e.g: - Gram-negative bacilli are normally unaffected by penicillin G - M. tuberculosis is insensitive to tetracyclines. • This resistance does not pose a significant clinical problem.
  6. 6. ACQUIRED RESISTANCE :- • It is the development of resistance by an organism (which was sensitive before) due to the prolonged use of an AMA. • Some bacteria are notorious for rapid acquisition of resistance e.g. staphylococci, coliforms, tubercle bacilli.
  7. 7. RESISTANCE MECHANISMS :- BIOCHEMICAL MECHANISMS - • Antimicrobial resistance can develop at any one or more of steps in the process • Reduced entry of antibiotic into pathogen • Enhanced export of antibiotic by efflux pumps • Release of microbial enzymes that destroy the antibiotic
  8. 8. • Alteration of microbial proteins that transform pro-drugs to the effective moieties • Alteration of target proteins • Development of alternative pathways to those inhibited by the antibiotic
  9. 9.  Reduced Entry of Drug into Pathogen :- • Small polar molecules & antibiotics, enter the cell through protein channels called Porins. • Absence of, mutation in, or loss of a favored porin channel can slow the rate of drug entry into a cell or prevent entry altogether  reducing drug concentration at the target site. • If target is intracellular  mutation or phenotypic change that slows or abolishes this transport mechanism  resistance.
  10. 10.  Resistance Due to Reduced Affinity of Drug to Altered Target Structure :- • A reduced affinity of drug for its target or the enzyme that converts the prodrug to active drug. Such alterations may be due to  Mutation of the natural target (e.g., fluoroquinolone resistance)  Target modification (e.g., ribosomal protection type of resistance to macrolides and tetracyclines) Acquisition of a resistant form of the native, susceptible target (e.g., staphylococcal methicillin resistance caused by production of a low-affinity penicillin-binding protein)
  11. 11. • Examples :- • The penicillin-resistant gonococci are less permeable to penicillin G. • Chloroquine-resistant P. Falciparum accumulates less chloroquine.
  12. 12.  Resistance Due to Drug Efflux :- • Microorganisms can overexpress efflux pumps and then expel antibiotics to which their susceptible. • Five major systems of efflux pumps - The multidrug and toxic compound extruder (MATE) - The major facilitator superfamily (MFS) transporters - The small multidrug resistance (SMR) system - The resistance nodulation division (RND) exporters - ATP binding cassette (ABC) transporters
  13. 13. • Drug resistance to erythromycin, fluoroquinolones & Anti-malarial drugs are mediated through these Efflux pumps.
  14. 14.  Resistance Due to Destruction of Antibiotic :- • Drug inactivation is a common mechanism of drug resistance. • Bacterial resistance to aminoglycosides  aminoglycoside-modifying enzyme • β -lactam antibiotics  β -lactamase
  15. 15.  Hetero-resistance and Viral Quasi Species :- • It is said to be present when only a subset of the total microbial population is resistant. • Increased therapeutic failures and mortality is seen. • Viral evolution due to drug and immune pressure  Quasi species. • Quasi species are resistant to antiretroviral agents  failure of antiretroviral therapy.
  16. 16.  Resistance due to Enhanced Excision of incorporated drug :- • These drugs are incorporated into the viral DNA chain and cause chain termination. • E.g. Nucleoside reverse transcriptase inhibitors such as zidovudine are 2′-deoxyribonucleoside analogs  5′-triphosphate and compete with natural nucleotides.
  17. 17.  MUTATION – • Mutation and antibiotic selection of the resistant mutant are the molecular basis for development of resistance in many bacteria, viruses, and fungi. • Mutations are not caused by drug exposure. They occur as a survival advantage, when drug is present.
  18. 18. • Mutations may occur in the gene encoding (1) The target protein, altering its structure so that it no longer binds the drug (2) A protein involved in drug transport (3) A protein important for drug activation or inactivation (4) In a regulatory gene or promoter gene affecting expression of the target, a transport protein, or an inactivating enzyme
  19. 19. • Suboptimal dosing strategies  selective kill of the more susceptible population, which leaves the resistant isolates to flourish. • A single-step mutation  high degree of resistance. • The Multi-step mutation  clinically significant resistance. • E.g : Combination of pyrimethamine and sulfadoxine inhibits Plasmodium falciparum’s folate biosynthetic pathway via inhibition of dihydrofolate reductase (DHFR) by pyrimethamine and dihydropteroate synthetase (DHPS) by sulfadoxine.
  20. 20.  Hypermutable Phenotypes :- • The ability to protect genetic information from disintegrating and also to be flexible enough to allow genetic changes. • This is accomplished principally by the - Insertion of the correct base pair by DNA polymerase III - Proofreading by the polymerase - Postreplicative repair. • Mutator (Mut) phenotypes  antibiotic resistance .
  21. 21. Quorum sensing :- • Microbes communicate with each other and exchange signaling chemicals (Autoinducers) coordinate gene expression for virulence, conjugation, apoptosis, mobility and resistance. • QS signal molecules AHL, AIP, AI-2 & AI-3 have been identified in GM-ve bacteria • Gram-positive bacteria use processed oligo-peptides to communicate.
  22. 22. • Several QS inhibitors molecules have been synthesized  AHL, AIP, and AI-2 analogues  Potent Virulence inhibitors. • QS controls virulence factor production in Gram-positive human pathogens including S. aureus, Listeria monocytogenes, Enterococcus faecalis, and Clostridium perfringens • V. cholera, P. aeruginosa  Gram negative bacteria .
  23. 23.  GENE TRANSFER :- • Drug resistance may be acquired by passage of the trait vertically to daughter cells, but more commonly it is acquired by horizontal transfer of resistance by, - Transduction - Transformation - Conjugation
  24. 24. • Horizontal transfer of resistance genes is greatly facilitated by Mobile genetic elements Plasmids Transducing Transposable Integrons Gene phages elements cassettes Insertion sequences Transposons Transposable phages
  25. 25. • Insertion sequences do not encode resistance, but they function as sites for integration of other resistance-encoding elements. • Transposons are insertion sequences that also code for drug resistance & other function. • Transposon move between chromosome and plasmid thus “hitchhike” the resistant gene out of the host and into a recipient.
  26. 26.  Transduction - Is acquisition of bacterial DNA from a phage that has incorporated DNA from a previous resistant host bacterium. e.g. strains of S. aureus.
  27. 27. Transformation - Is the uptake and incorporation into the host genome by free DNA released into the environment by other bacterial cells. E.g. Penicillin resistance in Pneumococci and Neisseria.
  28. 28. Conjugation - Is gene transfer by direct cell-to-cell contact through a sex pilus or bridge. • Multiple resistance genes can be transferred in a single event. • Genetic transfer by conjugation is common among gram-negative bacilli, and Enterococci.
  29. 29. CROSS RESISTANCE :- • Acquisition of resistance to one AMA conferring resistance to another AMA to which the organism has not been exposed e.g. - resistance to one sulfonamide means resistance to all others, -resistance to one tetracycline means insensitivity to all others • Partial cross resistance is sometimes seen in unrelated drugs e.g. - between tetracyclines and chloramphenicol - between erythromycin and lincomycin.
  30. 30. • Cross resistance may be  Two-way, e.g. between erythromycin and clindamycin and vice versa  One-way, e.g. development of neomycin resistance by enterobacteriaceae makes them insensitive to streptomycin but many streptomycin-resistant organisms remain susceptible to neomycin.
  31. 31. Prevention of drug resistance :-  No indiscriminate and inadequate or unduly prolonged use of AMAs should be made.  Prefer rapidly acting and selective (narrow spectrum) AMAs.  Use combination of AMAs for prolonged therapy e.g. tuberculosis, SABE.  Intensive treatment for notorious organisms.
  32. 32. REFERENCES :- • Essentials of Medical Pharmacology Sixth Edition - KD TRIPATHI MD • Goodman & Gilman’s The Pharmacological Basis of THERAPEUTICS • LaSarre B, Federle MJ. Exploiting Quorum Sensing To Confuse Bacterial Pathogens. Microbiology and Molecular Biology Reviews : MMBR. 2013;77(1):73-111. doi:10.1128/MMBR.00046-12.