SalmonellaTyphimurium (S. Tm) evades the innate immune response by residing within host phagocytes. To identify inhibitors of intracellularS. Tm growth, we performed parallel chemical screens againstS. 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 intracellularS. Tm. Screening of aS. Tm deletion library in the presence of one compound, metergoline, revealed that outer membrane perturbation enhanced activityin vitro. Combined with our observation of atypical cell surface characteristics of intracellularS. 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 systemicS. Tm infection. This work highlights the predictive nature of intracellular screens forin vivoefficacy, and uncovers new aspects of bacterial physiology of intracellularS. Tm.