MOLECULAR BASIS OF ANTIBIOTIC RESISTANCE, GENETIC MECHANISM AND THERAPEUTIC STRATEGIES

Abstract

Antibiotic resistance has become a global health crisis, driven by transferable resistance genes and diverse molecular mechanisms. Bacteria evade antibiotics through three core strategies: preventing drug access, altering or protecting targets, and directly inactivating drugs (e.g., via β-lactamases). Despite the clinical success of β-lactams—over 40 variants widely used—bacterial enzymes now threaten their utility. Even β-lactamase inhibitors are losing effectiveness as resistant mutants emerge. Genetic mechanisms include mutations and horizontal gene transfer. Biochemically, resistance arises through drug inactivation (β-lactamases, acetylases, phosphorylases), target modification (altered penicillin-binding proteins), permeability changes, and active efflux pumps. Clinically significant examples include enterococci (intrinsic and acquired resistance to multiple drug classes) and staphylococci (altered PBPs and β-lactamase expression). The transfer of glycopeptide resistance from enterococci to staphylococci is particularly concerning. Antimicrobial resistance (AMR) emerges from overuse in human medicine, veterinary practice, and agriculture, creating selection pressure. Multidrug resistance (MDR) involves genomic duplication, enzymatic modification, target alteration, membrane modulation, and efflux pumps, leading to treatment failures. New therapeutic directions include antivirulent therapy, antimicrobial peptides, phage therapy, vaccines, and nanoparticles. Combating AMR requires antimicrobial susceptibility testing, rapid diagnostics, timely clinical response, and novel pharmacodynamic approaches. The genetic plasticity of bacterial pathogens—through mutations and gene acquisition—has enabled resistance to nearly all clinical antibiotics. Understanding biochemical and genetic fundamentals is essential to reduce resistance transmission and develop effective therapies against multidrug-resistant organisms. Without urgent action, we face an era where common bacterial infections may become untreatable.