A new class of penicillin-binding protein inhibitors to address drug-resistant .

β-Lactams are the most widely used antibiotics for the treatment of bacterial infections because of their proven track record of safety and efficacy. However, susceptibility to β-lactam antibiotics is continually eroded by resistance mechanisms. Emerging multidrug-resistant (MDR) strains possessing altered alleles (encoding PBP2) pose a global health emergency as they threaten the utility of ceftriaxone, the last remaining outpatient antibiotic. Here we disclose a novel benzoxaborinine-based penicillin-binding protein inhibitor series (boro-PBPi) that is envisioned to address mediated resistance while offering protection against evolution and expansion of β-lactamases. Optimization of boro-PBPi led to the identification of compound (VNRX-14079) that exhibits potent antibacterial activity against MDR achieved by high affinity binding to the PBP2 target. Boro-PBPi/PBP2 complex structures confirmed covalent interaction of the boron atom with Ser310 and the importance of the β-β loop for improved affinity. elicits bactericidal activity, a low frequency of resistance, a good safety profile, suitable pharmacokinetic properties, and in vivo efficacy in a murine infection model against ceftriaxone-resistant . is a promising anti-gonorrhea agent poised for further advancement.