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

これはPDB形式変換不可エントリーです。

9MD0 の概要

• エントリーDOI: 10.2210/pdb9md0/pdb
• 分子名称: 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)
• 機能のキーワード: neisseria gonorrhoeae cephalosporin resistance penicillin-binding protein 2 boronate inhibitor, ligase
• 由来する生物種: Neisseria gonorrhoeae 35/02
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35883.68

構造登録者

Stratton, C.M.,Bala, S.,Davies, C. (登録日: 2024-12-05, 公開日: 2025-01-22)

主引用文献

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

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: 39763734
DOI: 10.1101/2024.12.27.630553

実験手法

X-RAY DIFFRACTION (2.613 Å)