The Novel DNA Binding Mechanism of Ridinilazole, a Precision Clostridiodes difficile Antibiotic
Clostridioides difficile infection (CDI) causes substantial morbidity and mortality worldwide with limited antibiotic treatment options. Ridinilazole is a precision bisbenzimidazole antibiotic being developed to treat CDI and reduce unacceptably high rates of infection recurrence in patients. Althou...
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Published in | Antimicrobial agents and chemotherapy Vol. 67; no. 5; p. e0156322 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Microbiology
17.05.2023
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Subjects | |
Online Access | Get full text |
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Summary: | Clostridioides difficile infection (CDI) causes substantial morbidity and mortality worldwide with limited antibiotic treatment options. Ridinilazole is a precision bisbenzimidazole antibiotic being developed to treat CDI and reduce unacceptably high rates of infection recurrence in patients. Although in late clinical development, the precise mechanism of action by which ridinilazole elicits its bactericidal activity has remained elusive. Here, we present conclusive biochemical and structural data to demonstrate that ridinilazole has a primary DNA binding mechanism, with a co-complex structure confirming binding to the DNA minor groove. Additional RNA-seq data indicated early pleiotropic changes to transcription, with broad effects on multiple C. difficile compartments and significant effects on energy generation pathways particularly. DNA binding and genomic localization was confirmed through confocal microscopy utilizing the intrinsic fluorescence of ridinilazole upon DNA binding. As such, ridinilazole has the potential to be the first antibiotic approved with a DNA minor groove binding mechanism of action. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors declare a conflict of interest. C.S.M., T.A., C.C., E.D., N.N., M.M., and D.J.P. are employees of and/or hold stock/stock options in Summit Therapeutics. Work contributed by K.R.F. was funded through a research collaboration agreement between University of Southampton and Summit Therapeutics. Work contributed by S. M. and S. R. was funded through a research collaboration agreement between Domainex Ltd and Summit Therapeutics. Work contributed by C.H., K.B., K.G., M.J.A., E.B., and K.W.G. was funded through a research collaboration agreement between University of Houston and Summit Therapeutics. K.W.G. has additional research funding paid to his university from Acurx Pharmaceuticals, Paratek Pharmaceuticals, and Seres Health. |
ISSN: | 0066-4804 1098-6596 1098-6596 |
DOI: | 10.1128/aac.01563-22 |