Antimicrobial resistance (AMR) has emerged as a critical global health challenge, supported in part by bacterial taxa that act as reservoirs of resistance determinants, facilitating their dissemination across microbial communities under antibiotic selective pressure. Among the diverse mechanisms underlying AMR, enzyme-mediated resistance plays a dominant role. These enzymes typically inactivate antibiotics or modify their targets by transferring specific functional groups or hydrolyzing the antibiotic molecules. Recent evolutionary pressures have fostered the emergence of bifunctional resistance enzymes, which provide simultaneous protection against multiple antibiotic classes and significantly enhance bacterial fitness. The remarkable diversity of these enzymes largely arises from divergent evolution, which has produced extensive enzyme superfamilies within bacterial systems. Collectively, they encompass a wide range of molecules that execute distinct resistance strategies, thereby fortifying microbial survival. To drive the discovery of novel therapeutics, it is essential to elucidate the expression patterns, structural dynamics, and functional mechanisms of these enzymes. Recent advances in omics technologies have transformed our capacity to investigate microbial defence systems, offering deep, high-throughput insights into the molecular underpinnings of resistance. This review provides an overview of critical resistance enzymes responsible for antibiotic modification and target protection in human-associated bacterial pathogens. Enhancing our understanding of these mechanisms is essential for developing next-generation therapeutics, including antibiotic potentiators, to effectively combat bacterial drug resistance.
Babele et al. (2026) studied this question.