Presented By: Center for the Discovery of New Medicines - CDNM
Drug Discover Lecture Series: “A novel family of natural products that targets uropathogenic Escherischia coli iron acquisition”
Laura Mike, Ph.D., Research Fellow, Microbiology and Immunology, University of Michigan
Learn about finding therapeutic agents to treat urinary tract infections by screening U-M’s collection of natural product extracts.
Urinary tract infections (UTIs) affect 1 in 40 women and are primarily caused by uropathogenic Escherichia coli (UPEC). The rate of resistance to antibiotics used to treat UTIs has steadily risen, highlighting the need for new antibiotic scaffolds and therapeutic strategies to treat UTIs.
Iron, an essential nutrient used as a co-factor in many biological processes, is dramatically lower in the bladder as compare to serum. It is not surprising then that UPEC strains deficient in iron acquisition are attenuated, suggesting that UPEC would be sensitive to drugs that block iron acquisition. To identify novel scaffolds and validate bacterial iron acquisition as a therapeutic target, we have screened 33,000 marine microbial-derived natural product extracts (NPEs) against an unmodified UPEC clinical isolate. This ensured that screening hits were not susceptible to Gram-negative efflux pumps. We identified 204 NPEs that reduce wild-type UPEC growth in low iron by over 90% without chelating iron or impacting bacterial viability in iron-replete medium. From these hits, we have purified a novel family of cyclic natural products that inhibit bacterial growth at nanomolar concentrations.
Preliminary data suggest that these small molecules are interacting with siderophore biosynthesis enzymes. These exciting data provide the foundation for exploring the structure-activity relationships of these compounds with their bacterial targets, which will inform the development of antimicrobial therapies that target iron homeostasis in UPEC and other Gram-negative bacteria.
Hosted by Vincent E. Groppi, Ph.D., CDNM Director
Urinary tract infections (UTIs) affect 1 in 40 women and are primarily caused by uropathogenic Escherichia coli (UPEC). The rate of resistance to antibiotics used to treat UTIs has steadily risen, highlighting the need for new antibiotic scaffolds and therapeutic strategies to treat UTIs.
Iron, an essential nutrient used as a co-factor in many biological processes, is dramatically lower in the bladder as compare to serum. It is not surprising then that UPEC strains deficient in iron acquisition are attenuated, suggesting that UPEC would be sensitive to drugs that block iron acquisition. To identify novel scaffolds and validate bacterial iron acquisition as a therapeutic target, we have screened 33,000 marine microbial-derived natural product extracts (NPEs) against an unmodified UPEC clinical isolate. This ensured that screening hits were not susceptible to Gram-negative efflux pumps. We identified 204 NPEs that reduce wild-type UPEC growth in low iron by over 90% without chelating iron or impacting bacterial viability in iron-replete medium. From these hits, we have purified a novel family of cyclic natural products that inhibit bacterial growth at nanomolar concentrations.
Preliminary data suggest that these small molecules are interacting with siderophore biosynthesis enzymes. These exciting data provide the foundation for exploring the structure-activity relationships of these compounds with their bacterial targets, which will inform the development of antimicrobial therapies that target iron homeostasis in UPEC and other Gram-negative bacteria.
Hosted by Vincent E. Groppi, Ph.D., CDNM Director
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