Mechanisms of antimicrobial resistance: From genetic evolution to clinical manifestations

Antimicrobial resistance (AMR) is a significant global health challenge that threatens the effectiveness of antibiotics and other antimicrobial agents. Here, we examined the molecular mechanisms that contribute to bacterial resistance, including alterations at target sites, enzymatic inactivation, efflux pump overexpression, and biofilm formation. Key resistance determinants, such as <i>bla</i> _CTX-M-15, <i>bla</i> _NDM-1, <i>mecA</i>, and <i>erm</i> genes, mediate enzymatic degradation and target modification, thereby diminishing antibiotic potency. Clinically significant pathogens, including <i>Escherichia coli</i>, <i>Pseudomonas aeruginosa</i>, <i>Klebsiella pneumoniae</i>, <i>Staphylococcus aureus</i>, and <i>Enterococcus faecium</i>, exemplify a broad spectrum of resistance and frequently acquire these traits through horizontal gene transfer (HGT), facilitated by plasmids, integrons, and transposons. The propensity for biofilm formation further augments bacterial persistence by impeding antimicrobial penetration and fostering intra-community genetic exchanges. The clinical ramifications of AMR are profound, contributing to elevated morbidity and mortality, extended hospitalization, and increased rates of therapeutic failure, all of which exert significant strain on the healthcare system. The economic consequences are equally severe, with escalating healthcare expenditures and substantial projected losses to the global gross domestic product (GDP). Addressing these challenges necessitates the adoption of advanced approaches, including genomic surveillance, antimicrobial stewardship, novel inhibitors targeting resistance pathways, immuno-antibiotics, and bacteriophage therapy. This review underscores the need to integrate molecular diagnostics and a One Health perspective to monitor and contain resistance across human, animal, and environmental reservoirs. A comprehensive understanding of the molecular and epidemiological aspects of AMR is essential for driving advancements in diagnostics, therapeutics, and policies, thereby ensuring global health protection.