7UT5

Acinetobacter baumannii dihydroorotate dehydrogenase bound with inhibitor DSM186

7UT5 の概要

• エントリーDOI: 10.2210/pdb7ut5/pdb
• 分子名称: Dihydroorotate dehydrogenase (quinone), (4R)-7-methyl-N-[4-(pentafluoro-lambda~6~-sulfanyl)phenyl]imidazo[1,2-a]pyrimidin-5-amine, FLAVIN MONONUCLEOTIDE, ... (6 entities in total)
• 機能のキーワード: inhibitor, complex, flavoprotein, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 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: 78801.67

構造登録者

Deng, X.,Phillips, M.,Tomchick, D. (登録日: 2022-04-26, 公開日: 2022-12-28, 最終更新日: 2023-10-25)

主引用文献

Russo, T.A.,Umland, T.C.,Deng, X.,El Mazouni, F.,Kokkonda, S.,Olson, R.,Carlino-MacDonald, U.,Beanan, J.,Alvarado, C.L.,Tomchick, D.R.,Hutson, A.,Chen, H.,Posner, B.,Rathod, P.K.,Charman, S.A.,Phillips, M.A.
Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii.
Proc.Natl.Acad.Sci.USA, 119:e2213116119-e2213116119, 2022

PubMed Abstract: New antimicrobials are needed for the treatment of extensively drug-resistant . The de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated drug target for malaria and human autoimmune diseases. We provide genetic evidence that DHODH (DHODH) is essential for bacterial survival in rodent infection models. We chemically validate the target by repurposing a unique library of ~450 triazolopyrimidine/imidazopyrimidine analogs developed for our malaria DHODH program to identify 21 compounds with submicromolar activity on DHODH. The most potent (DSM186, DHODH IC 28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverse strains, including meropenem-resistant isolates. A structurally related analog (DSM161) with a long in vivo half-life conferred significant protection in the neutropenic mouse thigh infection model. Encouragingly, the development of resistance to these compounds was not identified in vitro or in vivo. Lastly, the X-ray structure of DHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential of DHODH as a drug target for the development of antimicrobials for the treatment of and potentially other high-risk bacterial infections.

PubMed: 36512492
DOI: 10.1073/pnas.2213116119

実験手法

X-RAY DIFFRACTION (1.4 Å)