The σE-Hfq pathway is responsible for maintaining the integrity of the cell membrane under cell stress which is important for virulence or viability in gram-negative bacteria. Hfq is a chaperone that helps regulate outer membrane protein mRNAs. Small molecule inhibitors of the σE-Hfq pathway identified from a high-throughput screen, and natural products isolated from Hawaii, were analyzed using a cell-based fluorescence assay to identify those that specifically target the Hfq pathway.