Computer-aided drug design to generate a unique antibiotic family.

Autor: Barden CJ; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Wu F; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Fernandez-Murray JP; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Lu E; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Sun S; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Taylor MM; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Rushton AL; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Williams J; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Tavasoli M; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Meek A; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Reddy AS; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Doyle LM; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Sagamanova I; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Sivamuthuraman K; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada., Boudreau RTM; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada., Byers DM; Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, NS, Canada., Weaver DF; Krembil Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada.; Department of Chemistry, University of Toronto, Toronto, ON, Canada.; Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada., McMaster CR; Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. Christopher.mcmaster@dal.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 27; Vol. 15 (1), pp. 8317. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1038/s41467-024-52797-2
Abstrakt: The World Health Organization has identified antibiotic resistance as one of the three greatest threats to human health. The need for antibiotics is a pressing matter that requires immediate attention. Here, computer-aided drug design is used to develop a structurally unique antibiotic family targeting holo-acyl carrier protein synthase (AcpS). AcpS is a highly conserved enzyme essential for bacterial survival that catalyzes the first step in lipid synthesis. To the best of our knowledge, there are no current antibiotics targeting AcpS making this drug development program of high interest. We synthesize a library of > 700 novel compounds targeting AcpS, from which 33 inhibit bacterial growth in vitro at ≤ 2 μg/mL. We demonstrate that compounds from this class have stand-alone activity against a broad spectrum of Gram-positive organisms and synergize with colistin to enable coverage of Gram-negative species. We demonstrate efficacy against clinically relevant multi-drug resistant strains in vitro and in animal models of infection in vivo including a difficult-to-treat ischemic infection exemplified by diabetic foot ulcer infections in humans. This antibiotic family could form the basis for several multi-drug-resistant antimicrobial programs.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: