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

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.