Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant <i>Acinetobacter baumannii</i>.

Abstract

New antimicrobials are needed for the treatment of extensively drug-resistant <i>Acinetobacter baumannii</i>. 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 <i>A. baumannii</i> DHODH (<i>Ab</i>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 <i>Ab</i>DHODH. The most potent (DSM186, DHODH IC₅₀ 28 nM) had a minimal inhibitory concentration of ≤1 µg/ml against geographically diverse <i>A. baumannii</i> 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 <i>Ab</i>DHODH bound to DSM186 was solved to 1.4 Å resolution. These data support the potential of <i>Ab</i>DHODH as a drug target for the development of antimicrobials for the treatment of <i>A. baumannii</i> and potentially other high-risk bacterial infections.