DESCRIPTION (provided by applicant): There is a critical need for novel therapeutics to treat antimicrobial-resistant Gram-negative bacteria. Historically, antibiotics were identified in screen using whole bacteria. Over the past 20 years, there has instead been intensive biochemical screening that targets bacterial molecules, an approach that has often identified compounds with significant barriers in either the pathogen or the mammalian host, including an inability to enter or remain within host or pathogen cells, destruction by the host or pathogen, or host cytotoxicity. We have therefore developed a quantitative, image-based high content screen that excludes compounds with undesirable properties because it uses whole, virulent, bacteria growing within mammalian cells. We propose to use this screen to identify therapeutics that target nonessential bacterial virulence factors and will be effective against antimicrobial-resistant bacteria.

PUBLIC HEALTH RELEVANCE: Across the globe, multi-drug resistant (MDR) bacterial strains cause significant morbidity and mortality; there is an urgent need for new antibiotics, including those that target conserved virulence determinants of Gram-negative pathogens. We propose a screen to identify such compounds.