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

  • Nat Microbiol. 2026 May;11(5):1348-1360. doi: 10.1038/s41564-026-02309-3.
Tsuyoshi Uehara  1 ,  Allison L Zulli  #  2 ,  Brittany Miller  #  2 ,  Lindsay M Avery  2 ,  Steven A Boyd  2 ,  Cassandra L Chatwin  2 ,  Guo-Hua Chu  2 ,  Anthony S Drager  2 ,  Mitchell Edwards  2 ,  Susan G Emeigh Hart  2 ,  Nathan J Line  2 ,  Cullen L Myers  2 ,  Gopinath Rongala  2 ,  Annie Stevenson  2 ,  Kyoko Uehara  2 ,  Fan Yi  2 ,  Bibo Wang  3 ,  Zhenwu Liu  3 ,  Mingyue Wang  3 ,  Zhichao Zhao  3 ,  Xinming Zhou  3 ,  Haiyan Zhao  3 ,  Caleb M Stratton  4 ,  Sandeepchowdary Bala  4 ,  Christopher Davies  4 ,  Rok Tkavc  5  6 ,  Ann E Jerse  6 ,  Daniel C Pevear  2  7 ,  Christopher J Burns  2 ,  Denis M Daigle  2 ,  Stephen M Condon  8
Affiliations
  • 1. Venatorx Pharmaceuticals, Inc., Malvern, PA, USA. [email protected].
  • 2. Venatorx Pharmaceuticals, Inc., Malvern, PA, USA.
  • 3. BioDuro-Sundia, Beijing, China.
  • 4. Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, USA.
  • 5. Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
  • 6. Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 7. Spring Mill Pharma Inc., Malvern, PA, USA.
  • 8. Venatorx Pharmaceuticals, Inc., Malvern, PA, USA. [email protected].
  • # Contributed equally.
PMID: 41951974 DOI: 10.1038/s41564-026-02309-3
Abstract

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.

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