6MPQ

1.95 Ang crystal structure of OXA-24/40 beta-lactamase in complex the inhibitor ETX2514

6MPQ の概要

• エントリーDOI: 10.2210/pdb6mpq/pdb
• 分子名称: Beta-lactamase, (2S,5R)-1-formyl-3-methyl-5-[(sulfooxy)amino]-1,2,5,6-tetrahydropyridine-2-carboxamide, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: beta-lactamase, inhibitor, complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 28048.56

構造登録者

van den Akker, F.,Kumar, V. (登録日: 2018-10-08, 公開日: 2019-02-27, 最終更新日: 2023-11-15)

主引用文献

Barnes, M.D.,Kumar, V.,Bethel, C.R.,Moussa, S.H.,O'Donnell, J.,Rutter, J.D.,Good, C.E.,Hujer, K.M.,Hujer, A.M.,Marshall, S.H.,Kreiswirth, B.N.,Richter, S.S.,Rather, P.N.,Jacobs, M.R.,Papp-Wallace, K.M.,van den Akker, F.,Bonomo, R.A.
Targeting Multidrug-ResistantAcinetobacterspp.: Sulbactam and the Diazabicyclooctenone beta-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent.
MBio, 10:-, 2019

PubMed Abstract: Multidrug-resistant (MDR) spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded β-lactamases, including class C -derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A β-lactamases. Importantly, OXA-like β-lactamases represent a gap in the spectrum of inhibition by recently approved β-lactamase inhibitors such as avibactam and vaborbactam. ETX2514 is a novel, rationally designed, diazabicyclooctenone inhibitor that effectively targets class A, C, and D β-lactamases. We show that addition of ETX2514 significantly increased the susceptibility of clinical isolates to sulbactam. AdeB and AdeJ were identified to be key efflux constituents for ETX2514 in The combination of sulbactam and ETX2514 was efficacious against carrying , , , and in a neutropenic murine thigh infection model. We also show that, , ETX2514 inhibited ADC-7 (/ 1.0 ± 0.1 × 10 M s) and OXA-58 (/ 2.5 ± 0.3 × 10 M s). Cocrystallization of ETX2514 with OXA-24/40 revealed hydrogen bonding interactions between ETX2514 and residues R261, S219, and S128 of OXA-24/40 in addition to a chloride ion occupied in the active site. Further, the C3 methyl group of ETX2514 shifts the position of M223. In conclusion, the sulbactam-ETX2514 combination possesses a broadened inhibitory range to include class D β-lactamases as well as class A and C β-lactamases and is a promising therapeutic candidate for infections caused by MDR spp. The number and diversity of β-lactamases are steadily increasing. The emergence of β-lactamases that hydrolyze carbapenems poses a significant threat to our antibiotic armamentarium. The explosion of OXA enzymes that are carbapenem hydrolyzers is a major challenge (carbapenem-hydrolyzing class D [CHD]). An urgent need exists to discover β-lactamase inhibitors with class D activity. The sulbactam-ETX2514 combination demonstrates the potential to become a treatment regimen of choice for spp. producing class D β-lactamases.

PubMed: 30862744
DOI: 10.1128/mBio.00159-19

実験手法

X-RAY DIFFRACTION (1.95 Å)