Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii
Year: 2022
Type: article
Abstract: 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 ( Ab 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 Ab DHODH. The most potent (DSM186, DHODH IC 50 28 nM) had a minimal inhibitory concentration of ≤1 µg/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 Ab DHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential of Ab DHODH as a drug target for the development of antimicrobials for the treatment of A. baumannii and potentially other high-risk bacterial infections.
Institutions: Buffalo VA Medical Center, VA Western New York Healthcare System, University at Buffalo, State University of New York, Hauptman-Woodward Medical Research Institute, The University of Texas Southwestern Medical Center, University of Washington, Roswell Park Comprehensive Cancer Center, Monash University
Language: English
Subfield: Molecular Medicine
Domain: Life Sciences
Open Access status: hybrid
Funders: U.S. Department of Energy, U.S. Department of Veterans Affairs, Welch Foundation, University of Chicago, University of Texas Southwestern Medical Center, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Biological and Environmental Research, Argonne National Laboratory
Awards: G102163711, G1055550527, G107546177, Single Crystal X-ray Diffractometer equipped with Hybrid Pixel Array Detector and In Situ Crystallization Plate Screening Cap, G1313983767, G1664757510, G1842887323, G2026356871, G262962599, G2658435745, G2857925935, G3075337988, G4218573223, Determining the value of PBP 7/8 as an antimicrobial target for XDR-A. baumannnii, G5607048534, G6848031779, G7700305938, G8439083816, G9000214203, G969889393
OpenAlex ID: W4311258345