A macrophage-based screen identifies antibacterial compounds selective for intracellular Salmonella Typhimurium

Michael J. Ellis, Caressa N. Tsai, Jarrod W. Johnson, Shawn French, Wael Elhenawy, Steffen Porwollik, Helene Andrews-Polymenis, Michael McClelland, Jakob Magolan, Brian K. Coombes () and Eric D. Brown ()
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Michael J. Ellis: McMaster University
Caressa N. Tsai: McMaster University
Jarrod W. Johnson: McMaster University
Shawn French: McMaster University
Wael Elhenawy: McMaster University
Steffen Porwollik: University of California Irvine
Helene Andrews-Polymenis: Texas A&M University
Michael McClelland: University of California Irvine
Jakob Magolan: McMaster University
Brian K. Coombes: McMaster University
Eric D. Brown: McMaster University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.

Date: 2019
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DOI: 10.1038/s41467-018-08190-x

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