Antibiotic Resistance Flashcards
What is the effect of antibiotic resistance?
- Increases mortality
- Challenges control of infectious diseases
- Threatens a return to the pre-antibiotic era
- Increases the costs of health care
- Jeopardises health-care gains to society
Are drug resistant bacteria more pathogenic?
NO
-we just have fewer antibiotic options for treatment
Mechanisms of antibiotic resistance
Drug Inactivating Enzymes Altered/New Target Efflux Pump Intrinsic Impermeability Overproduction of Target Metabolic By-Pass
Drug Inactivating Enzymes
β-lactamase
-acquired by bacteria which destroys β-lactam and make antibiotic inactive
How do we kill bacteria which acquire β-lactamase?
Develop drugs which are resistant to β-lactamases, but then bacteria acquire extended spectrum β-lactamases which will even break down the antibiotics resistant to β-lactamase
How can an altered or new target lead to antibiotic resistance?
Drug target can be mutated and therefore the drug can no longer bind to its target, or bacteria can acquire new targets:
- Ribosome mutation
- Porins→ mutated or new porin expression prevents transport of antibiotics
- DNA gyrase mutation → quinolones won’t work
- RNA polymerase mutation → rifampicin won’t work
- Mcr1 & collistin
- PBPs (penicillin binding proteins) for peptidoglycan synthesis → PBP no longer inhibited by the β-lactam (MRSA acquires PB2a)
How do efflux pumps confer antibiotic resistance?
Bacteria can up-regulate genes which encode efflux pumps or acquire new efflux pumps, resulting in more efflux activity than there is influx of drug, meaning the drug doesn’t accumulate on the inside of bacteria sufficiently to achieve the MIC
Intrinsic impermeability and antibiotic resistance
Some bacteria (especially gram-ve) have membranes that are so impermeable that they are resistant to a whole range of antibiotics
*not due to any mutations, just the natural structure of bacteria
How does overproduction of target lead to antibiotic resistance?
· Bacteria can overcome the effect of competitive inhibitors (antibiotics) in the folic acid synthesis pathway (sulphonamides and trimethoprim) by upregulating the genes that encode for enzymes which produce folic acid, meaning there is more enzyme than there is competitive inhibitor and bacteria produce folic acid
· Bacteria can also induce the metabolic pathways which lead to increase in the synthesis of PABA, precursor for the synthesis of folic acid
Metabolic By-Pass and antibiotic resistance
· Vancomycin antibiotic binds D-ala D-ala terminal residues on the peptidoglycan precursor and prevents incorporation of the peptides into the growing peptidoglycan chain
· Bacteria resistant to vancomycin have acquired a whole set of genes that encode a new biosynthetic pathway which generates a D-ala D-lac terminal on the peptidoglycan precursor to which vancomycin can’t bind
Natural mechanisms of antibiotic resistance
Drugs can’t overcome natural barriers, porin, export pumps of bacteria
Genetic mechanisms of antibiotic resistance
Chromosome Mediated
-spontaneous mutation in the target molecule of drug uptake system
Plasmid Mediated
- acquisition of genes via conjugation
- common in gram-negative rods
Amongst sensitive bacteria, a spontaneous random mutation arises. As soon as an antibiotic is added, all the bacteria without the mutation die and the mutants survive and become resistant to antibiotic → selection of antibiotic resistant bacteria
How are genes transferred in bacteria?
There are 3 mechanisms by which bacteria exchange genetic information which encode drug resistance:
1) Transformation→ uptake of naked DNA from a bacteria which has lysed, taken up by another bacteria
2) Transduction → bacteriophage infects bacteria, taking a bit of DNA from the previous bacterial host and takes it to the next bacterial host
3) Conjugation → two bacterial cells come together and from a pili, through which chromosomal or plasmid DNA is exchanged
Methods by which bacteria develop resistance to β-lactam antibiotics
- Contain β-lactamase enzymes (Penicillinase)
- Acquire a new PBP or mutated PBP (MRSA acquires PB2a)
- Acquire a new porin or mutated porin
- Acquire a new efflux pump or mutated efflux pump
Action of β-lactamase
Penicillinase (β-lactamase) destroys active part of penicillin molecule (β-lactam ring). Antibiotic drug is therefore no longer a competitive structural mimic of the enzymes.
What is Augmentin/Co-amoxiclav?
Amoxicillin (β-lactam antibiotic) + Clavulanic acid (no antibacterial activity)
Action of Vancomycin
binds to terminal D-ala D-ala residues, blocking the enzymes involved in the cross-linking between D-ala D-ala and the long peptidoglycan chain, preventing incorporation of peptides into the growing peptidoglycan (no cross-linking)
How do bacteria achieve vancomycin resistance?
Metabolic By-Pass:
-acquired van operon by transposition, which is a whole set of genes that regulate the biosynthesis of precursor D-ala D-lactate. This prevents vancomycin binding.
