Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 20, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.06.025
Keywords
Antibiotic resistance; Target validation; DNA repair; Drug synergy; IMP-1700
Funding
- Engineering and Physical Sciences Research Council through an Engineering, Medicine, Natural Sciences and Physical Sciences Bridging Research in Antimicrobial resistance: Collaboration and Exchange (EMBRACE) pump-priming award [EP/M027007/1]
- Medical Research Council [MR/J006874/1]
- Wellcome Trust through an Imperial Confidence in Concept award
- Shionogi Co., Ltd.
- National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC)
- Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) Program: under NIAID/NIH Contract [HHSN272200700055C]
- EPSRC [EP/M027007/1, EP/N002474/1] Funding Source: UKRI
- MRC [2042385, MR/P028225/1, MC_PC_17162, MR/J006874/1] Funding Source: UKRI
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The global emergence of antibiotic resistance is one of the most serious challenges facing modern medicine. There is an urgent need for validation of new drug targets and the development of small molecules with novel mechanisms of action. We therefore sought to inhibit bacterial DNA repair mediated by the AddAB/RecBCD protein complexes as a means to sensitize bacteria to DNA damage caused by the host immune system or quinolone antibiotics. A rational, hypothesis-driven compound optimization identified IMP-1700 as a cell-active, nanomolar potency compound. IMP-1700 sensitized multidrug-resistant Staphylococcus aureus to the fluoroquinolone antibiotic ciprofloxacin, where resistance results from a point mutation in the fluoroquinolone target, DNA gyrase. Cellular reporter assays indicated IMP-1700 inhibited the bacterial SOS-response to DNA damage, and compoundfunctionalized Sepharose successfully pulled-down the AddAB repair complex. This work provides validation of bacterial DNA repair as a novel therapeutic target and delivers IMP-1700 as a tool molecule and starting point for therapeutic development to address the pressing challenge of antibiotic resistance.
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