Issue 25, 2024

Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance

Abstract

Antimicrobial resistance (AMR) is a growing threat to health globally, with the potential to render numerous medical procedures so dangerous as to be impractical. There is therefore an urgent need for new molecules that function through novel mechanisms of action to combat AMR. The bacterial DNA-repair and SOS-response pathways promote survival of pathogens in infection settings and also activate hypermutation and resistance mechanisms, making these pathways attractive targets for new therapeutics. Small molecules, such as IMP-1700, potentiate DNA damage and inhibit the SOS response in methicillin-resistant S. aureus; however, understanding of the structure–activity relationship (SAR) of this series is lacking. We report here the first comprehensive SAR study of the IMP-1700 scaffold, identifying key pharmacophoric groups and delivering the most potent analogue reported to date, OXF-077. Furthermore, we demonstrate that as a potent inhibitor of the mutagenic SOS response, OXF-077 suppresses the rate of ciprofloxacin resistance emergence in S. aureus. This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.

Graphical abstract: Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance

Supplementary files

Article information

Article type
Edge Article
Submitted
09 feb 2024
Accepted
07 maj 2024
First published
16 maj 2024
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2024,15, 9620-9629

Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance

J. D. Bradbury, T. Hodgkinson, A. M. Thomas, O. Tanwar, G. La Monica, V. V. Rogga, L. J. Mackay, E. K. Taylor, K. Gilbert, Y. Zhu, A. Y. Sefton, A. M. Edwards, C. J. Gray-Hammerton, G. R. Smith, P. M. Roberts, T. R. Walsh and T. Lanyon-Hogg, Chem. Sci., 2024, 15, 9620 DOI: 10.1039/D4SC00995A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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