8GK7

MsbA bound to cerastecin C

8GK7 の概要

• エントリーDOI: 10.2210/pdb8gk7/pdb
• EMDBエントリー: 40180
• 分子名称: Lipid A export ATP-binding/permease protein MsbA, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, 2-[(4-butylbenzene-1-sulfonyl)amino]-5-[(3-{4-[(4-butylbenzene-1-sulfonyl)amino]-3-carboxyanilino}-3-oxopropyl)carbamoyl]benzoic acid (3 entities in total)
• 機能のキーワード: msba, antibacterial, inhibitor, cerastecin, antimicrobial protein
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 135578.44

構造登録者

Chen, Y.,Klein, D. (登録日: 2023-03-17, 公開日: 2024-04-24, 最終更新日: 2025-05-21)

主引用文献

Wang, H.,Ishchenko, A.,Skudlarek, J.,Shen, P.,Dzhekieva, L.,Painter, R.E.,Chen, Y.T.,Bukhtiyarova, M.,Leithead, A.,Tracy, R.,Babaoglu, K.,Bahnck-Teets, C.,Buevich, A.,Cabalu, T.D.,Labroli, M.,Lange, H.,Lei, Y.,Li, W.,Liu, J.,Mann, P.A.,Meng, T.,Mitchell, H.J.,Mulhearn, J.,Scapin, G.,Sha, D.,Shaw, A.W.,Si, Q.,Tong, L.,Wu, C.,Wu, Z.,Xiao, J.C.,Xu, M.,Zhang, L.K.,McKenney, D.,Miller, R.R.,Black, T.A.,Cooke, A.,Balibar, C.J.,Klein, D.J.,Raheem, I.,Walker, S.S.
Cerastecins inhibit membrane lipooligosaccharide transport in drug-resistant Acinetobacter baumannii.
Nat Microbiol, 9:1244-1255, 2024

PubMed Abstract: Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.

PubMed: 38649414
DOI: 10.1038/s41564-024-01667-0

実験手法

ELECTRON MICROSCOPY (3.32 Å)