9MD0
Crystal structure of the transpeptidase domain of PBP2 from the Neisseria gonorrhoeae cephalosporin decreased susceptibility strain 35/02 in complex with boronate inhibitor VNRX-6752
This is a non-PDB format compatible entry.
Summary for 9MD0
| Entry DOI | 10.2210/pdb9md0/pdb |
| Descriptor | Penicillin-binding protein 2, (3R)-3-({(2R)-2-(4-carboxyphenyl)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]acetyl}amino)-2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid (3 entities in total) |
| Functional Keywords | neisseria gonorrhoeae cephalosporin resistance penicillin-binding protein 2 boronate inhibitor, ligase |
| Biological source | Neisseria gonorrhoeae 35/02 |
| Total number of polymer chains | 1 |
| Total formula weight | 35883.68 |
| Authors | |
| Primary citation | Uehara, T.,Zulli, A.L.,Miller, B.,Avery, L.M.,Boyd, S.A.,Chatwin, C.L.,Chu, G.H.,Drager, A.S.,Edwards, M.,Emeigh Hart, S.G.,Myers, C.L.,Rongala, G.,Stevenson, A.,Uehara, K.,Yi, F.,Wang, B.,Liu, Z.,Wang, M.,Zhao, Z.,Zhou, X.,Zhao, H.,Stratton, C.M.,Bala, S.,Davies, C.,Tkavc, R.,Jerse, A.E.,Pevear, D.C.,Burns, C.J.,Daigle, D.M.,Condon, S.M. A new class of penicillin-binding protein inhibitors to address drug-resistant Neisseria gonorrhoeae. Biorxiv, 2024 Cited by PubMed Abstract: 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) strains possessing altered 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 mediated resistance while offering protection against evolution and expansion of β-lactamases. Optimization of boro-PBPi led to the identification of compound (VNRX-14079) that exhibits potent antibacterial activity against MDR 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 β-β loop for improved affinity. 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 . is a promising anti-gonorrhea agent poised for further advancement. PubMed: 39763734DOI: 10.1101/2024.12.27.630553 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.613 Å) |
Structure validation
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