Bacterial pathogens must resist host innate immunity to cause disease. While Gram-negative bacteria have a protective outer membrane, this membrane is subject to host-induced damage that makes these pathogens vulnerable. We developed a high content screening platform that identifies compounds that cause the killing of the bacterial pathogen Salmonella enterica in macrophages. This platform enables the rapid discovery of compounds that work in concert with the macrophage to prevent pathogen survival, as most hit compounds are not active in standard microbiological media and are not pro-drugs. We describe within the platform and the compounds it has found, and consider how they may help us discover new ways to fight infection.