{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T14:54:20Z","timestamp":1768488860680,"version":"3.49.0"},"posted":{"date-parts":[[2024,12,27]]},"group-title":"Microbiology","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T00:00:00Z","timestamp":1735257600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,12,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  \u03b2-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 \u03b2-lactam antibiotics is continually eroded by resistance mechanisms. Emerging multidrug-resistant (MDR)\n                  <jats:italic>Neisseria gonorrhoeae<\/jats:italic>\n                  strains possessing altered\n                  <jats:italic>penA<\/jats:italic>\n                  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\n                  <jats:italic>penA-<\/jats:italic>\n                  mediated resistance while offering protection against evolution and expansion of \u03b2-lactamases. Optimization of boro-PBPi led to the identification of compound\n                  <jats:bold>21<\/jats:bold>\n                  (VNRX-14079) that exhibits potent antibacterial activity against MDR\n                  <jats:italic>N. gonorrhoeae<\/jats:italic>\n                  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 \u03b2\n                  <jats:sub>3<\/jats:sub>\n                  -\u03b2\n                  <jats:sub>4<\/jats:sub>\n                  loop for improved affinity.\n                  <jats:bold>21<\/jats:bold>\n                  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                  <jats:italic>N. gonorrhoeae<\/jats:italic>\n                  .\n                  <jats:bold>21<\/jats:bold>\n                  is a promising anti-gonorrhea agent poised for further advancement.\n                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