Bradbury Jacob D, Hodgkinson Thomas, Thomas Adam M, Tanwar Omprakash, La Monica Gabriele, Rogga Vanessa V, Mackay Luke J, Taylor Emilia K, Gilbert Kiera, Zhu Yihua, Sefton Amber Y, Edwards Andrew M, Gray-Hammerton Charlotte J, Smith Gerald R, Roberts Paul M, Walsh Timothy R, Lanyon-Hogg Thomas
Department of Pharmacology, University of Oxford OX1 3QT UK
Ineos Oxford Institute for Antimicrobial Research, Sir William Dunn School of Pathology, University of Oxford OX1 3RE UK.
Chem Sci. 2024 May 16;15(25):9620-9629. doi: 10.1039/d4sc00995a. eCollection 2024 Jun 26.
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 ; 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 . This work supports SOS-response inhibitors as a novel means to combat AMR, and delivers OXF-077 as a tool molecule for future development.
抗菌耐药性（AMR）对全球健康构成了日益严重的威胁，有可能使众多医疗程序变得极其危险而无法实施。因此，迫切需要通过新的作用机制发挥作用的新分子来对抗AMR。细菌DNA修复和SOS反应途径促进病原体在感染环境中的存活，还会激活超突变和耐药机制，使这些途径成为新疗法的有吸引力的靶点。小分子，如IMP-1700，可增强DNA损伤并抑制耐甲氧西林菌中的SOS反应；然而，目前缺乏对该系列结构-活性关系（SAR）的了解。我们在此报告了对IMP-1700支架的首次全面SAR研究，确定了关键药效基团，并提供了迄今为止报道的最有效的类似物OXF-077。此外，我们证明，作为诱变SOS反应的有效抑制剂，OXF-077可抑制环丙沙星耐药性在……中的出现率。这项工作支持将SOS反应抑制剂作为对抗AMR的一种新手段，并将OXF-077作为未来开发的工具分子。
