Mechanisms of Antimicrobial Resistance

Introduction & framing

• Drug resistance — the unresponsiveness of a microorganism to an antimicrobial agent (AMA) to which it was originally sensitive — analogous to tolerance in higher organisms.
• An inevitable evolutionary consequence — antimicrobial use applies selection pressure that preserves random genomic variants permitting survival; today every major antibiotic class is associated with significant resistance. Antibiotics act in concert with host immunity, so microbial elements that blunt the immune response can mimic resistance clinically.
• Two orthogonal axes — every resistant strain is described on two independent axes — a biochemical axis (how the drug is defeated) and a genetic axis (where the determinant came from). More than one mechanism often operates in one isolate, and a single phenotype can be reached by several molecular routes.
• Biochemical axis (G&G three-tier scheme) — resistance arises at any step by which a drug reaches and combines with its target: (1) reduced concentration at the target (impermeability + efflux); (2) enzymatic alteration / destruction of the drug; (3) target modification reducing affinity — plus less-common routes (metabolic bypass, target overproduction, excision of drug–target complexes).
• Genetic axis — the determinant is either intrinsic / natural (pre-existing, species-level) or acquired — the latter by mutation–selection (vertical) or horizontal gene transfer (infectious resistance).