Learning Objective
Describe emerging mechanisms of bacterial resistance to major classes of antimicrobial agents, including altered drug targets, enzymatic inactivation, efflux, and permeability changes, and identify clinically relevant examples.
Inhibitors of Cell Wall Synthesis
| Drug Class |
Mechanism |
Example Organisms |
| β-lactams |
Variable outer membrane (chromosome-mediated) |
Pseudomonas aeruginosa (ceftazidime) |
|
Mutant/new PBPs (chromosome-mediated) |
S. pneumoniae (penicillin), H. influenzae (ampicillin), S. aureus (methicillin), N. gonorrhoeae (penicillin) |
|
β-lactamases (plasmid-mediated) |
S. aureus, H. influenzae, N. gonorrhoeae, Klebsiella, Enterobacter spp. |
| Glycopeptides |
Increased cell wall thickness (chromosome-mediated) |
VISA (S. aureus) |
|
Amino acid substitution (chromosome/plasmid-mediated) |
Enterococcus faecalis, E. faecium (vancomycin), S. aureus (VRSA) |
| Isoniazid |
Mutation of the catalase-peroxidase gene (chromosome-mediated) |
Mycobacterium tuberculosis |
| Ethambutol |
Mutation of the arabinosyl transferase gene (chromosome-mediated) |
M. tuberculosis |
Inhibitors of Protein Synthesis
| Drug Class |
Mechanism |
Example Organisms |
| Aminoglycosides |
Efflux / oxidative transport (plasmid) |
P. aeruginosa (gentamicin) |
|
Ribosomal binding site mutation (chromosome) |
Enterococcus (gentamicin) |
|
Enzymatic modification (adenylation, acetylation, phosphorylation) |
Klebsiella, Enterobacter spp. |
| Macrolides / Lincosamides |
Minimal outer membrane penetration (chromosome) |
Gram (−) |
|
Efflux pump (plasmid) |
Gram (+) cocci, erythromycin |
|
23S rRNA methylation (plasmid) |
Bacteroides fragilis, S. aureus (MLS resistance) |
|
Enzymatic inactivation (phosphotransferase, esterase, plasmid) |
Gram (+) cocci |
| Chloramphenicol |
Acetyltransferase (plasmid-mediated) |
Salmonella |
| Tetracyclines |
Efflux pump (plasmid/transposon) |
Widespread, including animal feed isolates |
|
Ribosomal protection protein (plasmid or chromosome) |
S. aureus |
Inhibitors of Nucleic Acid Synthesis
| Drug Class |
Mechanism |
Example Organisms |
| Fluoroquinolones |
Efflux pump (plasmid); permeability mutation (chromosome) |
Enterococcus, Pseudomonas |
|
Mutant topoisomerase (chromosome) |
E. coli, P. aeruginosa (ciprofloxacin) |
| Rifamycins |
Mutant RNA polymerase (chromosome) |
M. tuberculosis, S. aureus, N. meningitidis |
| Folate inhibitors |
Altered DHPS or DHFR (chromosome) |
Enterobacteriaceae (sulfonamides) |
Notes on Resistance Mechanisms
- Gram-positive β-lactamases: Exoenzymes, low activity against cephalosporins, methicillin, or oxacillin.
- Gram-negative β-lactamases: Periplasmic, may have penicillinase and cephalosporinase activity. ESBLs are inducible and include multiple cephalosporins; TEM-1 is the most common.
- Vancomycin resistance genes (vanA, vanB): Transposon-mediated; can transfer from Enterococcus to MDR plasmids in S. aureus.
- MLS resistance: Methylation of 23S rRNA imparts resistance to macrolides, lincosamides, and streptogramins.
Activity
