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

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 similar to 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 mu g/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 angstrom 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.

Automated summary

New antimicrobials are necessary for treating extensively drug-resistant Acinetobacter baumannii. The results of genetic and chemical studies suggest that the de novo pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is essential for the survival of this bacterium. By repurposing a library of analogs developed for malaria DHODH program, researchers have identified 21 compounds with potent activity against Acinetobacter baumannii DHODH. One of these compounds, DSM186, has shown promise with minimal inhibitory concentrations against various strains of A. baumannii. These findings highlight the potential of DHODH as a target for the development of new antimicrobials for the treatment of high-risk bacterial infections.