Targeting DNA gyrase B: medicinal chemistry strategies to combat antimicrobial resistance.

Abstract

Antimicrobial resistance (AMR) represents one of the most pressing global healthcare challenges, necessitating the discovery of novel antibacterial agents with distinct mechanisms of action. DNA gyrase, an essential bacterial type II topoisomerase absent in humans, has emerged as an attractive antibacterial target. In particular, the ATPase domain of the GyrB subunit is highly conserved across ESKAPE pathogens, providing a strong rationale for the development of broad-spectrum antibacterial agents. Several natural product-derived antibiotics, including novobiocin, clorobiocin, and coumermycin A1, are well-established GyrB inhibitors that share a common 3-amino-4-hydroxycoumarin pharmacophore responsible for key interactions with residues such as Glu50, Arg76, Pro79, and Arg136 within the ATP-binding pocket. To improve potency and overcome resistance, diverse medicinal chemistry strategies, including scaffold hopping, bioisosteric replacement, linker rigidification, and pharmacophore hybridization, have been employed to develop novel ATP-competitive GyrB inhibitors. These approaches have led to compounds with enhanced enzyme inhibition, improved suppression of bacterial DNA supercoiling, and superior minimum inhibitory concentration (MIC) values. This review comprehensively summarizes the design, synthesis, biological evaluation, and structure-activity relationships of heterocyclic GyrB inhibitors, highlighting the therapeutic potential of quinoline, thiazole, pyrrole, benzimidazole, benzofuran, azaindole, benzothiazole, pyrazole, pyridine, and related scaffolds. In addition, recent advances in resistance mechanisms, translational challenges, and clinically advanced GyrB inhibitors are discussed, providing a comprehensive perspective to guide the rational design of next-generation antibacterial agents for combating antimicrobial resistance.