VNRX-14079

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)Neisseria gonorrhoeaestrains possessing alteredpenAalleles (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 addresspenA-mediated resistance while offering protection against evolution and expansion of β-lactamases. Optimization of boro-PBPi led to the identification of compound21(VNRX-14079) that exhibits potent antibacterial activity against MDRN. gonorrhoeaeachieved 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 β3-β4loop for improved affinity.21elicits 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-resistantN. gonorrhoeae.21is a promising anti-gonorrhea agent poised for further advancement.