TY - JOUR
T1 - Repurposed dihydroorotate dehydrogenase inhibitors with efficacy against drug-resistant Acinetobacter baumannii
AU - Russo, Thomas A.
AU - Umland, Timothy C.
AU - Deng, Xiaoyi
AU - Mazouni, Farah El
AU - Kokkonda, Sreekanth
AU - Olson, Ruth
AU - Carlino-MacDonald, Ulrike
AU - Beanan, Janet
AU - Alvarado, Cassandra L.
AU - Tomchick, Diana R.
AU - Hutson, Alan
AU - Chen, Hong
AU - Posner, Bruce
AU - Rathod, Pradipsinh K.
AU - Charman, Susan A.
AU - Phillips, Margaret A.
N1 - Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS.
PY - 2022/12/20
Y1 - 2022/12/20
N2 - 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.
AB - 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.
KW - Acinetobacter baumannii
KW - antimicrobial resistance
KW - dihydroorotate dehydrogenase
KW - drug discovery
KW - pyrimidine metabolism
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U2 - 10.1073/pnas.2213116119
DO - 10.1073/pnas.2213116119
M3 - Article
C2 - 36512492
AN - SCOPUS:85144379392
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 51
M1 - e2213116119
ER -