Chapter 35  ·  Module 11

Bacterial Resistance Mechanisms

Four major categories: enzymatic inactivation, target modification, efflux/permeability, and horizontal gene transfer

Abbreviations: MRSA = methicillin-resistant S. aureus  |  VRE = vancomycin-resistant Enterococcus  |  ESBL = extended-spectrum beta-lactamase  |  KPC = Klebsiella pneumoniae carbapenemase  |  NDM = New Delhi metallo-beta-lactamase  |  MBL = metallo-beta-lactamase  |  MLSB = macrolide-lincosamide-streptogramin B  |  HGT = horizontal gene transfer  |  RND = resistance-nodulation-division

Category 1 — Enzymatic Inactivation

Beta-Lactamases

Hydrolysis of Beta-Lactam Ring

Narrow-Spectrum
  • TEM-1, SHV-1: hydrolyze penicillins and early cephalosporins only
ESBL (Extended-Spectrum)
  • Hydrolyze all cephalosporins + aztreonam; NOT carbapenems
  • Inhibited by clavulanic acid, tazobactam
  • Main producers: E. coli, K. pneumoniae
  • Use carbapenems for serious ESBL bacteremia
Carbapenemases
  • KPC (class A serine) — most prevalent in US
  • NDM, VIM, IMP (MBL class B) — resist all serine inhibitors
  • OXA-48 (class D) — Europe and Middle East
  • Aztreonam + avibactam active vs. many MBL producers
AmpC
  • Inducible cephalosporinase; resists classical inhibitors
  • Enterobacter, Serratia, Pseudomonas — avoid 3rd-gen cephalosporins

Other Inactivating Enzymes

Aminoglycoside and Chloramphenicol Enzymes

Aminoglycoside-Modifying Enzymes
  • Acetyltransferases, phosphotransferases, nucleotidyltransferases
  • Modify aminoglycoside → cannot bind 30S ribosomal subunit
  • Enzyme specificity varies: some affect gentamicin but not amikacin
  • Amikacin often active when gentamicin is resistant
Chloramphenicol Acetyltransferase
  • Acetylates hydroxyl groups → cannot bind 50S subunit
  • Plasmid-encoded; primary mechanism of chloramphenicol resistance

Category 2 — Target Modification and Bypass

MRSA

PBP2a — Altered Target

  • mecA gene → PBP2a with low beta-lactam affinity
  • All other PBPs inhibited; PBP2a continues cross-linking
  • Ceftaroline/ceftobiprole: 5th-gen cephalosporins active vs. PBP2a

VRE

D-Ala-D-Lac — Target Bypass

  • vanA/vanB → D-Ala-D-Lac replaces D-Ala-D-Ala
  • Vancomycin affinity reduced ~1,000-fold
  • vanA: resistance to vancomycin + teicoplanin; transferable
  • vanB: vancomycin only; not teicoplanin

Ribosomal & Enzyme Targets

Methylation and Mutations

MLSB (erm genes)
  • 23S rRNA methylation → cross-resistance to macrolides, clindamycin, strep B
  • Inducible form: D-zone positive → avoid clindamycin
Fluoroquinolones
  • Point mutations in DNA gyrase (GyrA) and topoisomerase IV (ParC)
  • Sequential mutations required for high-level resistance

Category 3 — Efflux and Permeability

Efflux Pumps

Active Drug Extrusion

RND Family (Gram-negatives)
  • Tripartite: inner membrane pump + adapter + outer membrane channel
  • AcrAB-TolC (E. coli); MexAB-OprM (P. aeruginosa)
  • Efflux fluoroquinolones, beta-lactams, tetracyclines, chloramphenicol
  • Regulatory mutation → overexpression → MDR without gene acquisition
MFS Family (Gram-positives)
  • NorA in S. aureus — contributes to fluoroquinolone resistance

Permeability Barriers

Porin Loss

Outer Membrane Porins
  • Hydrophilic antibiotics (beta-lactams, fluoroquinolones, carbapenems) enter via porins
  • Porin loss + efflux overexpression = synergistic resistance
Clinical Examples
  • Porin loss + ESBL/AmpC → non-carbapenemase carbapenem resistance
  • P. aeruginosa: OprD loss → imipenem-resistant, meropenem-susceptible phenotype

Category 4 — Horizontal Gene Transfer

Mechanism How It Works Clinical Relevance
Conjugation Plasmid transfer via pilus (cell-to-cell) Most clinically important; transfers multiple resistance genes simultaneously; explains sudden multidrug resistance
Transformation Uptake of free DNA from lysed bacteria Important in naturally competent species (S. pneumoniae, H. influenzae)
Transduction Bacteriophage-mediated DNA transfer Relevant in staphylococci; less common than conjugation for clinical resistance spread
Transposons DNA segments that insert between chromosomes and plasmids Carry resistance genes between mobile elements; Tn1546 carries vanA
Integrons Capture resistance gene cassettes by site-specific recombination Class 1 integrons strongly associated with multidrug resistance in clinical isolates

Stewardship Principle

Use antibiotics only when genuinely indicated, with the narrowest effective spectrum, for the shortest proven duration. De-escalate from broad-spectrum empiric therapy to targeted narrow-spectrum therapy once susceptibility results are available. Every unnecessary course amplifies selection pressure for resistance.