7Z9P

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

Summary for 7Z9P

• Entry DOI: 10.2210/pdb7z9p/pdb
• Descriptor: DNA (5'-D(P*GP*CP*GP*AP*AP*TP*TP*CP*GP*CP*G*(RID))-3'), Ridinilazole, SULFATE ION, ... (6 entities in total)
• Functional Keywords: clostridiodes difficile, antibiotic, dna-binding, drug discovery, target identification, dna
• Biological source: synthetic construct (32630)
• Total number of polymer chains: 6
• Total formula weight: 23845.16

Authors

Mason, S.,Leonard, P.M. (deposition date: 2022-03-21, release date: 2023-03-29, Last modification date: 2024-02-07)

Primary citation

Mason, C.S.,Avis, T.,Hu, C.,Nagalingam, N.,Mudaliar, M.,Coward, C.,Begum, K.,Gajewski, K.,Alam, M.J.,Basseres, E.,Moss, S.,Reich, S.,Duperchy, E.,Fox, K.R.,Garey, K.W.,Powell, D.J.
The Novel DNA Binding Mechanism of Ridinilazole, a Precision Clostridiodes difficile Antibiotic.
Antimicrob.Agents Chemother., 67:e0156322-e0156322, 2023

PubMed 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.

PubMed: 37093023
DOI: 10.1128/aac.01563-22

Experimental method

X-RAY DIFFRACTION (2.2 Å)