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

Abstract

Salmonella Typhimurium (S. Tm) evades the innate immune response by residing within host phagocytes. To identify inhibitors of intracellular S. Tm growth, we performed parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. These screens identified novel antibacterials, and revealed that antibiotics with limited Gram-negative coverage are active against intracellular S. Tm. Screening of a S. Tm deletion library in the presence of one compound, metergoline, revealed that outer membrane perturbation enhanced activity in vitro. Combined with our observation of atypical cell surface characteristics of intracellular S. Tm, our work indicates that the bacterial outer membrane is permeabilized within macrophages. We show that metergoline targets the bacterial cytoplasmic membrane, and prolongs animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and uncovers new aspects of bacterial physiology of intracellular S. Tm.