9md0 | pdb_00009md0

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

spinqualitylabelsall models 9md0, resolution 2.61Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9md0 is a 1 chain structure with sequence from Neisseria gonorrhoeae 35/02. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.613Å Ligands: A1BJB Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8RR30_NEIGO Catalyzes cross-linking of the peptidoglycan cell wall at the division septum.[HAMAP-Rule:MF_02080] Publication Abstract from PubMed beta-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 beta-lactam antibiotics is continually eroded by resistance mechanisms. Emerging multidrug-resistant (MDR) Neisseria gonorrhoeae strains possessing altered penA 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 penA-mediated resistance while offering protection against evolution and expansion of beta-lactamases. Optimization of boro-PBPi led to the identification of compound 21 (VNRX-14079) that exhibits potent antibacterial activity against MDR N. gonorrhoeae 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 beta(3)-beta(4) loop for improved affinity. 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. 21 is a promising anti-gonorrhea agent poised for further advancement. A new class of penicillin-binding protein inhibitors to address drug-resistant Neisseria gonorrhoeae.,Uehara T, Zulli AL, Miller B, Avery LM, Boyd SA, Chatwin CL, Chu GH, Drager AS, Edwards M, Emeigh Hart SG, Myers CL, Rongala G, Stevenson A, Uehara K, Yi F, Wang B, Liu Z, Wang M, Zhao Z, Zhou X, Zhao H, Stratton CM, Bala S, Davies C, Tkavc R, Jerse AE, Pevear DC, Burns CJ, Daigle DM, Condon SM bioRxiv [Preprint]. 2024 Dec 27:2024.12.27.630553. doi: , 10.1101/2024.12.27.630553. PMID:39763734 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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