Computer-aided drug design to generate a unique antibiotic family

Christopher J. Barden, Fan Wu, J. Pedro Fernandez-Murray, Erhu Lu, Shengguo Sun, Marcia M. Taylor, Annette L. Rushton, Jason Williams, Mahtab Tavasoli, Autumn Meek, Alla Siva Reddy, Lisa M. Doyle, Irina Sagamanova, Kovilpitchai Sivamuthuraman, Robert T. M. Boudreau, David M. Byers, Donald F. Weaver and Christopher R. McMaster ()
Additional contact information
Christopher J. Barden: University Health Network, University of Toronto
Fan Wu: University Health Network, University of Toronto
J. Pedro Fernandez-Murray: Dalhousie University
Erhu Lu: University Health Network, University of Toronto
Shengguo Sun: University Health Network, University of Toronto
Marcia M. Taylor: University Health Network, University of Toronto
Annette L. Rushton: Dalhousie University
Jason Williams: Dalhousie University
Mahtab Tavasoli: Dalhousie University
Autumn Meek: University Health Network, University of Toronto
Alla Siva Reddy: University Health Network, University of Toronto
Lisa M. Doyle: University Health Network, University of Toronto
Irina Sagamanova: University Health Network, University of Toronto
Kovilpitchai Sivamuthuraman: University Health Network, University of Toronto
Robert T. M. Boudreau: Dalhousie University
David M. Byers: Dalhousie University
Donald F. Weaver: University Health Network, University of Toronto
Christopher R. McMaster: Dalhousie University

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52797-2

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