Abstact

Emerging multidrug-resistant Neisseria gonorrhoeae strains possessing altered penA alleles (encoding penicillin-binding protein 2, PBP2) threaten the utility of ceftriaxone, the last remaining outpatient antibiotic for gonorrhoea treatment, posing a global health emergency. Here we report a benzoxaborinine-based penicillin-binding protein inhibitor series (boro-PBPi) developed to address penA-mediated ceftriaxone resistance. Optimization of boro-PBPi led to the identification of compound 21 (VNRX-14079), which exhibited potent antibacterial activity against multidrug-resistant N. gonorrhoeae through high-affinity binding to the PBP2 target. Boro-PBPi-PBP2 complex structures confirmed the covalent interaction of the boron atom with the catalytic residue Ser310 and the importance of the beta(3)-beta(4) loop mobility for improved affinity. Boro-PBPi 21 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 N. gonorrhoeae. Boro-PBPi 21 is therefore a promising antigonorrhoea agent poised for further advancement.