7ut5

Acinetobacter baumannii dihydroorotate dehydrogenase bound with inhibitor DSM186

spinqualitylabelsall models 7ut5, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7ut5 is a 2 chain structure with sequence from Acinetobacter baumannii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.4Å Ligands: FMN, GOL, OBR, ORO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PYRD_ACIB3 Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor. Publication Abstract from PubMed New antimicrobials are needed for the treatment of extensively drug-resistant Acinetobacter baumannii. 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 A. baumannii DHODH (AbDHODH) 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 AbDHODH. The most potent (DSM186, DHODH IC(50) 28 nM) had a minimal inhibitory concentration of </=1 microg/ml against geographically diverse A. baumannii 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 AbDHODH bound to DSM186 was solved to 1.4 A resolution. These data support the potential of AbDHODH as a drug target for the development of antimicrobials for the treatment of A. baumannii and potentially other high-risk bacterial infections. Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii.,Russo TA, Umland TC, Deng X, El Mazouni F, Kokkonda S, Olson R, Carlino-MacDonald U, Beanan J, Alvarado CL, Tomchick DR, Hutson A, Chen H, Posner B, Rathod PK, Charman SA, Phillips MA Proc Natl Acad Sci U S A. 2022 Dec 20;119(51):e2213116119. doi: , 10.1073/pnas.2213116119. Epub 2022 Dec 13. PMID:36512492 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dihydroorotate dehydrogenase 3D structures

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