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Resistance to antimicrobial agents

Resistance to antimicrobial agents. Resistance to antimicrobial agents. Resistance to antimicrobial agents. Innate resistance (insensitivity) Phenotypic adaptation Mutation Antibiotic resistance genes Inactivation of antibiotic Active efflux of antibiotic Alteration of target site

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Resistance to antimicrobial agents

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  1. Resistance to antimicrobial agents

  2. Resistance to antimicrobial agents

  3. Resistance to antimicrobial agents • Innate resistance (insensitivity) • Phenotypic adaptation • Mutation • Antibiotic resistance genes • Inactivation of antibiotic • Active efflux of antibiotic • Alteration of target site • Metabolic bypass

  4. Mechanisms of antibiotic resistance Inactivation of antibiotic Active efflux of antibiotic Alteration of target Metabolic bypass

  5. O S R-C-NH CH3 CH3 O COOH -lactamase Resistance genes: Inactivation of antibiotics • -lactamases - Many different types • Occur in both Gram +ve and Gram -ve • Penicillin G introduced • Nearly all S.aureus sensitive when penicillin introduced • Now 90% human isolates resistant • Combat -lactamase • -lactamase resistant -lactams - eg methicillin • -lactamase inhibitors - clavulanic acid, sulbactam, tazobactam

  6. Resistance genes: Inactivation of antibiotics Chloramphenicol Aminoglycosides

  7. Resistance genes: Active efflux of antibiotics • Tetracycline-resistance and Macrolide-resistance • Efflux pump • cytoplasmic membrane protein that actively pumps antibiotic out of the cytoplasm

  8. Resistance genes: Alteration in target site • -lactams • Gene for altered penicillin binding protein (PBP) acquired from another organisms • eg. S.aureus MRSA • Macrolides • Chemical modification of antibiotic binding site • Resistance enzyme methylates 2 adenine residues on 23S rRNA • Prevents antibiotic binding

  9. Resistance genes: metabolic bypass • Sulphonamide and Trimethoprim resistance • Plasmid encoded enzymes (DHPS and DHFR) • Reduced affinity for sulphonamides and trimethoprim • Same affinity for PABA and DHF

  10. Evolution of antibiotic resistance bacteria • Resistance genes existed prior to the use of antibiotics • Organisms that live in the soil • Protection from antibiotics produced by soil microorganisms • Spread to clinically important bacteria • Huge use of antibiotics in agriculture, human and veterinary medicine selects for antibiotic resistance organisms

  11. Evolution of multi-R plasmids GentR AmpR LinR SulphR TetR

  12. Transfer of resistance genes • R-plasmids • Conjugation • Mainly Gram -ve bacteria • Tn carrying antiR genes insert into plasmids • Multiple resistance • Conjugative Transposons • Promote their own transfer to other bacteria • Insert into chromosome or plasmid in bacteria • Most important in Gram +ve bacteria

  13. Genetics of of antibiotic resistance Transformation Transduction Naked DNA Bacteriophage Conjugative plasmid Conjugation Transposon with AntiR gene Chromosome Conjugative transposon Mutation

  14. Where are the new antibiotics?

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