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.

Bradbury J.D., Hodgkinson T., Thomas A.M., Tanwar O., La Monica G., Rogga V.V., et al. (2024). Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance. CHEMICAL SCIENCE, 1-10 [10.1039/d4sc00995a].

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

La Monica G.;
2024-05-01

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.
mag-2024
Settore CHIM/08 - Chimica Farmaceutica
Bradbury J.D., Hodgkinson T., Thomas A.M., Tanwar O., La Monica G., Rogga V.V., et al. (2024). Development of an inhibitor of the mutagenic SOS response that suppresses the evolution of quinolone antibiotic resistance. CHEMICAL SCIENCE, 1-10 [10.1039/d4sc00995a].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/638578
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