Repurposing tavaborole to combat resistant bacterial infections through competitive inhibition of KPC-2 and metabolic disruption

Abstract

The rise of carbapenem-resistant Enterobacteriaceae (CRE) strains has emerged as an increasing threat to global public health. The development of antibiotic adjuvants presents an economical and promising approach to address this crisis. Through a high-throughput screen of the FDA-approved compound library, we identified tavaborole (AN2690) as a broad-spectrum β-lactamase inhibitor. The mechanistic study revealed that tavaborole formed a reversible binding with the active serine of KPC-2, showing effective competitive inhibition. Its electron-deficient boron atom formed a borate ester bond with hydroxyl group of the serine residue at the active site of KPC-2, transitioning to an sp3-hybridized state that mimicked the tetrahedral intermediate during KPC-2 catalytic. Moreover, transcriptomic analysis and bacterial metabolism assays further unveiled tavaborole addition can inhibit tricarboxylic acid (TCA) cycle, coupled with downregulation of intracellular ATP levels, indicating that tavaborole compromised the bacterial metabolic homeostasis and exerted synergistic antibacterial activity. Notably, the combination treatment further suppressed the development of meropenem resistance. In mouse intraperitoneal infection models, tavaborole effectively restored the efficacy of meropenem against CRE bacteria. These findings elucidate the synergistic mechanisms of tavaborole, expand its potential applications in anti-infection therapeutics, and provide a promising strategy for addressing CRE infections.