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.
Highlights
As macrophages are one of the primary host cell types manipulated by Salmonella for replication and systemic dissemination
Intracellular pathogens often occupy niches that are difficult to recapitulate in vitro; we and others have developed fluorescence, luminescence, and colorimetric-based screening assays with readouts that approximate bacterial viability when compared to traditional cfu counting methods[36,53,54,55,56]
We found that metergoline activity in vivo was potent in the cecum and colon, which is perhaps surprising given that the spleen and liver serve as the primary reservoirs for intraperitoneal S
Summary
This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella. Emerging evidence suggests that pathogens such as Staphylococcus aureus and Streptococcus pneumoniae are able to survive within host cells[4,5] In these intracellular environments, genes that are otherwise dispensable for growth in nutrient-rich media often become essential, constituting a novel antimicrobial target space that is currently underexplored[6]. Salmonella infections are commonly treated with fluoroquinolones, cephalosporins, or macrolides[12], cephalosporins do not penetrate phagocytic cells[13] Resistance to these antibiotic classes is increasing worldwide[14,15]. Tm that detect and respond to immune stresses with alterations in virulence gene expression[20]
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