Chemical GeneticsImage grid of bacteria under test conditions.

Small molecules that prevent bacterial replication in vivo.

How bacterial pathogens that live within professional phagocytes outwit innate immunity remains a black box. We developed an in-cell screen to identify chemicals that disrupt host-pathogen interactions. The screening platform is called SAFIRE, Screen for Anti-infectives using Fluorescence microscopy of IntracellulaR Enterobacteriaceae. SAFIRE uses macrophages infected with the human Gram-negative pathogen Salmonella enterica to identify small molecules that prevent bacterial replication or survival within mammalian cells.

Antibiotic Discovery

Inhibitors of Bacterial Efflux Pumps

We used SAFIRE to screen a drug-diversity library and identified three small molecules that are efflux pump modulators (EPMs). These EPMs kill bacteria in macrophages and in epithelial cells. In broth culture, the EPMs prevent export of efflux pump substrates by Salmonella, Klebsiella and Enterobacter clinical isolates that are antimicrobial resistant. In collaboration with Dr. Ed Yu’s laboratory, we found that the compounds bind a subunit of a clinically relevant efflux pump. We are currently optimizing analogs of these small molecules.

SAFIRE1Plot of bacteria growth.

Small Molecules That Target The Host

SAFIRE also identifies compounds that bolster host cell defenses and thereby reduce bacterial intracellular survival.