Technology Summary

Gram-negative bacteria are formidable pathogens because their cell envelope presents an adaptable barrier to environmental and host-mediated challenges. The stress response pathway, controlled by the alternative sigma factor sE, is critical for maintenance of the cell envelope. Because sE is required for the virulence or viability of several Gram-negative pathogens, including Enterobacteriaceae, it may represent a novel target for antibiotic development. No known antibiotics target the sE pathway. Using a patented high-throughput screening system, Penn State Inventors created and defined a novel suite of sE inhibitors that exhibit antibiotic activity and drug-like physical properties. Structure-activity relationship (SAR) studies assessed the importance of different functional groups for approximately 50 analogs. Compounds from the lead series show MIC levels of 1-3 µg/mL in E. coli. No cytotoxicity or CYP450 inhibition was observed. Drugs that emerge from these compounds have the potential to be used as stand-alone treatments or as supplements to traditional antibiotics. Inhibition of this pathway is novel.