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<p>Emerging multidrug-resistant <i>Neisseria gonorrhoeae</i> strains possessing altered <i>penA</i> 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 <i>penA</i>-mediated ceftriaxone resistance. Optimization of boro-PBPi led to the identification of compound 21 (VNRX-14079), which exhibited potent antibacterial activity against multidrug-resistant <i>N. gonorrhoeae</i> 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 β<sub>3</sub>–β<sub>4</sub> 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 <i>N. gonorrhoeae</i>. Boro-PBPi 21 is therefore a promising antigonorrhoea agent poised for further advancement.</p>

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A penicillin-binding protein inhibitor series to target drug-resistant Neisseria gonorrhoeae

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • Tsuyoshi Uehara,
  • Allison L. Zulli,
  • Brittany Miller,
  • Lindsay M. Avery,
  • Steven A. Boyd,
  • Cassandra L. Chatwin,
  • Guo-Hua Chu,
  • Anthony S. Drager,
  • Mitchell Edwards,
  • Susan G. Emeigh Hart,
  • Nathan J. Line,
  • Cullen L. Myers,
  • Gopinath Rongala,
  • Annie Stevenson,
  • Kyoko Uehara,
  • Fan Yi,
  • Bibo Wang,
  • Zhenwu Liu,
  • Mingyue Wang,
  • Zhichao Zhao,
  • Xinming Zhou,
  • Haiyan Zhao,
  • Caleb M. Stratton,
  • Sandeepchowdary Bala,
  • Christopher Davies,
  • Rok Tkavc,
  • Ann E. Jerse,
  • Daniel C. Pevear,
  • Christopher J. Burns,
  • Denis M. Daigle,
  • Stephen M. Condon

摘要

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 β3–β4 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.