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Antimicrobial Resistance Mechanisms and control

Genetic basis of antimicrobial resistance


1. Intrinsic resistance
2. Mutations
3. Acquisition of foreign DNA
Intrinsic resistance
Predict potential problems that may emerge under selective pressures
Stenotrophomonas maltophilia, environmental bacteria cause infection to IC
patients: intrinsically resistant imipenem
Enterococci: intrinsically resistant cephalosporins and amyloglycosides
Mutations
Significant clinical impact: emergence of resistance during therapy, resistance
develops on treatment
Acquisition
Transduction Acquire with help by flagella
Transformati Organisms acquire DNA which resists antibiotic from dead body
on
Conjugation
Acquire by direct contact
Mechanisms of antimicrobial resistance
1. Beta-lactam
6. Sulphonamides
2. Aminoglycosides
7. Trimethoprim
3. Glycopeptides
8. Tetracylines
4. Quinolones
9. Chloramphenicol
5. Marcolides

10. Beta-lactam
1. Enzymatic modification - Beta-lactamase (plasmid-mediated)
Plasmid: for containing genes, can cross species even genus
There are chromosome-mediated but slower and within species transfer only
Gram-negative bacteria (E. coli, Salmonella, etc)
(Beta-lactamase genes: TEM-1, OXA-1, etc)
2. Modification of penicillin binding proteins (mutation), which for cell wall synthesis
Penicillin-resistant Streptococcus pneumonia
Penicillin-resistant Neisseria gonorrhoeae, almost 100% resistant
3. Bypass resistance: alternative routes of peptidoglycan synthesis
Produce other PBPs which do not bind to penicillin to synthesis
Methicillin-resistant Staphylococcus aureus, mec gene
4. Impermeability: porin loss (mutation)
Porin loss to prevent antibiotics get in
Imipenem-resistant Pseudomonas aeruginosa
11. Aminoglycosides
1. Enzymatic modification:
aminoglycoside-modifying enzymes (AME) (plasmid-encoded)
Gram-negative bacteria
Gram-positive bacteria, both produce it
2. Ribosomal resistance
Rare
Mutations in ribosomal genes
High-level streptomycin resistance in enterococci
Streptomycin resistance in M. tuberculosis (low level: intrinsic,
aminoglycosides + penicillin synergistic effect
3. Ineffective transport
O2 transport system, no O2 transport system in anaerobes, so all anaerobes
are resistant to aminoglycosides
12. Glycopeptides
1. Permeability
Gram negative bacteria naturally resistant because glycopeptides are large
molecules, cannot pass through outer membrane porins
Vancomycin is effective on Gram positive bacteria only
2. Acquired vancomycin resistance
Genes encode ligases (for protein synthesis) which incorporate D-lactate in
place of D-alanine as terminal amino acid of the peptide chain affinity for
glycopeptides antibiotics
13. Quinolones
1. Mutations (most common)
DNA gyrase twist DNA chromosome into small packing & type 4
topoisomerase for DNA replication, mutation on gene coding for DNA gyrase &
type 4 DNA topoisomerase, both are target of quinolones
2. Altered permeability
quantities of OmpF outer membrane protein, OmpF is porin for quinolones
to get inside, Omp: outermembrane protein
3. Efflux
Efflux pumps
4. qnr
Qnr proteins protect DNA gyrase from binding of quinolones
5. Ciprofloxacin-modifying enzyme
14. Macrolides
1. Target site alternation:
Modification of 23S rRNA by methylase, encoded by a class of genes erm

(erythromycin ribosome methylation)


2. Drug modification:
macrolide-modifying enzymes
3. Altered transport (efflux)
4. permeability
15. Sulphonamides
1. Overproduction of para-aminobenzoic acid (PABA)
Compete with sulphonamides
2. Change in dihydropteroic acid synthetase enzyme
3. Mutations in chromosomal genes/ plasmid-mediated
4. cell permeability
16. Trimethoprim
1. Mutation in gene coding for production of dihydrofolate reductase (DHFR)
production of/ change in DHFR
2. Thymine auxotrophy
17. Bacteria cannot utilize exogenous thymine; gene mutation allows them to use it
3. cell permeability (loss of OMP)
4. Resistance genes integrated into transposons, on plasmid or chromosome
18.
19. Pteridine + PABA (dihydropteroic acid synthetase, target of sulphonamides)-->
dihydropteroic acid --> dihydrofolic acid (dihydrofolate reductase, DHFR, target of
trimethoprim)--> tetrahydrofolic acid --> thymidine
20. Tetracycline
1. Energy-dependent efflux
2. Enzymatic modification (rare)
3. Ribosomal protection proteins, target of tetracycline is ribosome
21. Chloramphenicol
1. Enzymatic modification
Chloramphenicol acetyltransferase (CAT): acetylated chloramphenicol cannot
bind to ribosome
2. Active efflux: Pseudomonas aeruginosa
22. Control
Resistance in natural, intestine of human & man
Resistance will develop whenever antibiotics are used
Avoid indiscriminate use in human, animals, think before use
Surveillance
Avoid sub-therapeutic doses which cannot kill bacteria and cause resistance,
selective pressure
Patient compliance, complete the course
New antibiotics with other modes of action