The novel DNA binding mechanism of ridinilazole, a precision Clostridiodes difficile antibiotic

DOI: 10.1128/aac.01563-22

Authors: Clive S. Mason (Summit Therapeutics) , Tim Avis (Summit Therapeutics) , Chenlin Hu (University of Houston College of Pharmacy) , Nabeetha Nagalingam (Summit Therapeutics) , Manikhandan Mudaliar (Summit Therapeutics) , Chris Coward (Summit Therapeutics) , Khurshida Begum (University of Houston College of Pharmacy) , Kathleen Gajewski (University of Houston College of Pharmacy) , M. Jahangir Alam (University of Houston College of Pharmacy) , Eugenie Bassères (University of Houston College of Pharmacy) , Stephen Moss (Domainex Ltd) , Stefanie Reich (Domainex Ltd) , Esther Duperchy (Summit Therapeutics) , Keith R. Fox (University of Southampton) , Kevin W. Garey (University of Houston College of Pharmacy) , David J. Powell (Summit Therapeutics)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Antimicrobial Agents And Chemotherapy

State: Published (Approved)
Published: April 2023

Abstract: 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.

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I04-Macromolecular Crystallography

Added On: 27/04/2023 09:02

Documents:
aac.01563-22.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)