A platform for predicting mechanism of action based on bacterial transcriptional responses identifies an unusual DNA gyrase inhibitor.

Autor:	French S; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Guo ABY; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Ellis MJ; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Deisinger JP; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Johnson JW; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Rachwalski K; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Piquette ZA; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Lluka T; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Zary M; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Gamage S; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Magolan J; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada., Brown ED; McMaster University, Department of Biochemistry and Biomedical Sciences and Michael G. DeGroote Institute for Infectious Disease Research, Hamilton, ON L8S 4L8, Canada. Electronic address: ebrown@mcmaster.ca.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Apr 23; Vol. 43 (4), pp. 114053. Date of Electronic Publication: 2024 Apr 04.
DOI:	10.1016/j.celrep.2024.114053
Abstrakt:	In the search for much-needed new antibacterial chemical matter, a myriad of compounds have been reported in academic and pharmaceutical screening endeavors. Only a small fraction of these, however, are characterized with respect to mechanism of action (MOA). Here, we describe a pipeline that categorizes transcriptional responses to antibiotics and provides hypotheses for MOA. 3D-printed imaging hardware PFIboxes) profiles responses of Escherichia coli promoter-GFP fusions to more than 100 antibiotics. Notably, metergoline, a semi-synthetic ergot alkaloid, mimics a DNA replication inhibitor. In vitro supercoiling assays confirm this prediction, and a potent analog thereof (MLEB-1934) inhibits growth at 0.25 μg/mL and is highly active against quinolone-resistant strains of methicillin-resistant Staphylococcus aureus. Spontaneous suppressor mutants map to a seldom explored allosteric binding pocket, suggesting a mechanism distinct from DNA gyrase inhibitors used in the clinic. In all, the work highlights the potential of this platform to rapidly assess MOA of new antibacterial compounds. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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