Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii

Thomas A. Russo, Timothy C. Umland, Xiaoyi Deng, Farah El Mazouni, Sreekanth Kokkonda, Ruth Olson, Ulrike Carlino-MacDonald, Janet Beanan, Cassandra L. Alvarado, Diana R. Tomchick, Alan Hutson, Hong Chen, Bruce Posner, Pradipsinh K. Rathod, Susan A. Charman, Margaret A. Phillips

Research output: Contribution to journalArticlepeer-review


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 IC50 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 AbDHODH bound to DSM186 was solved to 1.4 Å 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.

Original languageEnglish (US)
Article numbere2213116119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number51
StatePublished - Dec 20 2022


  • Acinetobacter baumannii
  • antimicrobial resistance
  • dihydroorotate dehydrogenase
  • drug discovery
  • pyrimidine metabolism

ASJC Scopus subject areas

  • General


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