Antibiotic Resistance Flashcards
What are the mechanisms by which antibiotic resistance occurs?
Drug inactivation e.g. beta-lactamase
Alter the target for the antibiotic or acquire a new target e.g. RNA polymerase undergoes mutation so Rifampin can no longer bind or a mutation in a porin gene so drugs can’t enter through porin
Bacteria can acquire genes that encode for efflux pumps or mutate already present efflux pumps that allows for the pumping out of drugs so the antibiotic concentration needed is never achieved
Overproduction of target such as trimethoprim, needed for folic acid synthesis, which means there’s not enough drug for the target and overcomes the inhibition
Intrinsic impermeability, just by the natural structure of the bacteria they have become impermeable to the antibiotic
Metabolic bypass, e.g. vancomycin, where some bacteria have developed peptidoglycan synthesis without a D-ala D-ala terminal, instead it has become D-ala D-lac so vancomycin can’t bind
How can we categorise paths to antibiotic resistance?
Directed at antibiotic itself - - Degrading the drug - Modifying the drug New or Altered target - antibiotic no longer binds - e.g. PBPs - PBP2a in MRSA Altered transport - Actively pumping drug out - efflux pump - porins no longer influx drug Metabolic by-pass - metabolic change D-ala-D-lac and vancomycin
What are the genetic mechanisms behind the development of antibiotic resistance?
Chromosome-mediated - Due to spontaneous mutation: · in the target molecule · in the drug uptake system Mutants are SELECTED; they are NOT induced Plasmid-mediated gene exchange - Common in Gram-negative bacteria - Transferred via conjugation - Multidrug resistance
What are the three ways gene transfer occurs in bacteria?
Mechanism for genetic heterogeneity and evolution
Rapid, cross-species
Can transfer virulence (toxins), drug resistance, antigens (immune evasion)
Transformation:
- Bacteria can take up DNA fragment from environment and can integrate it into its own DNA
Transduction:
- The transfer of genetic material through the use of bacteriophage which had already infected a bacteria and incorporated its genome into its phage head
- So when it infects the new host it will inject its own genome but also the genome it has acquired form the previous host into the bacterial cell
Conjunction:
- When two organisms come together and as a result of this conjugal tube, coded for by conjugal plasmids, that allows the genetic exchange from the donor bacteria to the recipient bacteria
How do gram+ve and -ve bacteria develop resistance to beta-lactams?
Gram + ve - ß-lactamase (Penicillinase) - Alteration of the transpeptidase enzyme (PBP) Gram - ve - ß -Lactamase (Penicillinase) - Alteration of porins
What is augmentin?
Binds to and inactivates beta-lactamases
Clavulanic acid binds to the beta-lactamase enzyme
No anti-bacterial activity of its own but amoxicillin comes in a destroys the bacteria
How what are the different ways bacteria would be resistant to beta-lactams?
If we get a mutations in the porin or a new porin type it will cause multi-drug resistance
If there is a mutation in the PBP the drug cannot bind or inactivate the enzymes in charge of peptidoglycan synthesis
In the third scenario, the drug can get in but the bacteria acquires a beta-lactamase enzyme which causes binding and degradation of beta-lactam
What are the different ways bacteria become resistant to penicillin?
Produce penicillinases / beta lactamases that cleave the beta lactam ring
- penicillin is inactivated
Acquire alternative forms of / or mutations in penicillin binding proteins (PBPs)
- penicillin can’t bind
Acquire alternative forms of / mutations in porins,
- penicillin cannot get into cell
Acquire alternative forms of / mutations in efflux pumps
- penicillins are pumped out faster
How do bacteria become resistant to vancomycin?
Acquisition of van operon by transposition
Makes D-ala-D-lactate - prevents vancomycin binding
What are the non-genetic mechanisms to antibiotic resistance?
Inaccessibility to drugs
- (e.g., abscess, TB lesion)
Stationary phase/vegetations and biofilms
- (non-susceptible to inhibitors of cell wall synthesis)
So in an in-vitro experiment the antibiotic would work fin
How do you prevent or overcome antibiotic resistance?
Control use - not in animal feeds - complete course [DOTS for TB] - appropriate prescribing New or modified drugs - few in past 25 years Combination therapy - different targets - overcome mutation rates Infection control - individual - ward - society Re-establish susceptible flora?
