6. Bacterial Genetics and Antibiotic Resistance Flashcards
What are the 4 bacterial targets for antibiotics (give abx examples)?
1. Cell wall biosynthesis - penicillins, cephalosporins, vancomycin
2. Protein biosynthesis - macrolides, aminoglycosides (e.g. gent), tetracyclines
3. DNA and RNA replication - rifampicin, ciprofloxacin
4. Folate metabolism (b/c bacteria make their own folic acid) - trimethoprim, sulphonamide
What are the 4 ways bacteria become resistant to antibiotics?
1. Mutation of drug target: rifampicin inhibits RNA pol and is bactericidal in many spp. Single nucleotide/aa change in outer membrane protein alters affinity for drug without affecting function. Several diff mutations can cause resistance (and also to streptomycin and ciprofloxacin). Thus use rifampicin in combiation with other drugs for TB, otherwise limit to prophylaxis or rare indications.
2. Breakdown of antibiotic: β-lactams inhibit CW synthesis, widely used, resistant bacteria degrade β-lactam - bacteria have acquired new gene for β-lactamase. Now have e.g. co-amoxiclav which contains a β-lactamase inhibitor.
3. Modification of antibiotic: bacteria acquire genes encoding aminoglycoside modifying enzymes, which add small molecules to the drug and prevent it binding
4. Efflux of antibiotic: tetracyline, chloramphenicol, fluoroquinolones and β-lactams can be evaded by efflux mechanisms (pumps can be specific or non). Bacteria may upregulate existing pump via mutation, or acquire genes for new pump
Describe the bacterial genome.
How do bacteria acquire resistance genes?
Haploid circular chromosome, often also extrachromosomal DNA in plasmids.
1. Conjugation: e.g. F (fertility) factors - F+ cells produce F pili which contact recipient, plasmid transfer involves replication so it’s not lost by donor. (pic)
2. Transformation: transfer of naked DNA from environment -> integrated into chromosome by homologous recombination. Replaces existing gene with resistant variant e.g. Strep pneumoniae penicillin resistance
3. Transposition via transposons: DNA sequences capable of excision insertion into new locations in chromosome or plasmid e.g. insertion sequences (IS) which encode transposase gene flanked by inverted repeats. Process gives duplication of target sequence. Can get complex/composite transposons with multiple genes e.g. each integron contains up to 5 gene cassettes, most abx resistance determinants e.g. oxa (β-lactam).
4. Mutation
5. Transduction: infection with ‘phage’ as vector
What are the activities of transposons?
What are ICE (integrative and conjugative elements)?
Where do resistance genes originate?
Why does resistance spread?
- Transfer genes plasmid -> plasmid
- Conjugative transposons transfer from cell -> cell
- Transfer genes plasmid -> chromosome
- Pick up chromosomal genes
Have features of transposon, plasmid and phage.
Abx are natural products e.g. penicllin from mould. Also get resistance to synthetic antimicrobials like sulphonamides
Rare events lead to resistance aquisition. Selection in presence of abx. Selection by 1 antibiotic can spread resistance to many - multiple resistance elements!
What is antimicrobial stewardship?
Cordinated program, promotes appropriate use of antimicrobials (including antibiotics), improves patient outcomes and adherence, reduce healthcare costs, reduces microbial resistance and adverse drug events, and decreases the spread of infections caused by multidrug-resistant organisms. Covers control of prescribing and other measures to reduce resistance.
