Objectives
- Understand the main classes of antibiotics and their mechanism of action
- Discuss the molecular mechanism of antibiotic resistance
- Discuss how antibiotic resistance spreads
- Be a good steward of antimicrobials
Chemotherapy, caesareans and joint replacements may become too dangerous if antibiotic resistance wins.
Mechanisms of resistance
1. Restricted access to target
Antibiotic must access its target.
Permeability
Bacteria can make it so that less drug can get into cell
for example ß-lactams must cross outer membranes of gram negatices and gram negatives are intrinsically resistant to vancomysin
an example of chagning permeability is by changing porins.
Efflux pump
Bacteria can pump out drug (active efflux pump)
2. Inactivation of antibiotic
Bacteria can change the antibiotic so it does not work.
an example of this is ß-lactamase. this catalyses the ß-lactam to its inactive state so it cannot inhibit penicillin binding protein
ß-lactamase inhibitors
this is a no u to the class A ß-lactamases as it bind irreversibly to the ß-lactamases
3. Modification of target
Theis the bacteria changing the target so the mechansim of action of the antibiotic is inhibited
An example of this is a new Penicillin binding protein which does not irreversibly bind to penicillin
or vancomysin resistant peptidoglycan side chains
Target modification through mutation (fluoroquinolone)
Mutation can just develop resistance during infection
Intrinsic vs acquired resistance
Intrinsic
- normally resistant to antimicrobial
- chromosomally encoded
- Examples:
- Vancomycin and gram-negatives
- chromosomal AmpC ß-Lactamase
Acquired
- Bacterial normally susceptable to antimicrobials
- Acquire resistance through gene acquisition or mutation
Spread of antimicrobial resistance
Often a route is as follows antibiotic mediated selection leads to drug resistant bacteria
drug resistance bacteria horizontally transfers resistance gene to other bacteria through 3 main ways
Gene transfer
-
Conjugation bacterial sex
-
transformation take up plasmid from environment
-
transduction phages take antimicrobial resistance with them