SC17: TECHNOLOGIES TO ASSESS PERMEABILITY AND EFFLUX IN GRAM NEGATIVE BACTERIAL PATHOGENS
THURSDAY, SEPTEMBER 27, 7:00 - 9:30 PM
Room: Berkeley

Our lack of understanding of the molecular basis for compound penetration into and efflux out of Gram-negative bacteria has been identified as a key bottleneck for the rational discovery of novel antibacterial compounds. A main driver of this knowledge gap is the historical lack of assays, tools, and/or predictive models to provide medicinal chemists with structure-activity relationships that could guide optimization of whole cell penetration (and efflux avoidance). However, there have been some recent, promising advances in the field which set the stage for future innovative approaches.

The course will cover:

• Overview of the challenging features inherent to Gram-negative cell envelopes
• Historical approaches to measuring compound uptake/accumulation
• Recent genetic and cell-based assays
• Recent label-free spectroscopic and mass spectrometry methods
• Recent methods for subcellular accumulation determination
• Future Prospects

Intended Audience:

This workshop is designed for scientists and physicians from academia, biotech, and pharma with an interest in antibiotic drug discovery.

Instructor Biographies:

David A. Six, Ph.D., Investigator III, Bacteriology Lead Discovery, Infectious Diseases, Novartis Institutes for BioMedical Research (NIBR)

David A. Six, Ph.D. is a Lab Head and Project Team Leader in the Bacteriology Lead Discovery Group in the NIBR Infectious Diseases Area. David leads multidisciplinary antibiotic discovery teams targeting multidrug resistant Gram-negative pathogens. The outer membrane permeability barrier and efflux are major challenges in developing novel agents with activity against Gram-negative pathogens. He leads several exploratory projects aimed at targets necessary for the formation and maintenance of the Gram-negative outer membrane permeability barrier. Notably, he has utilized novel technologies to create an internal platform to better characterize compound penetration and accumulation in bacteria. Prior to joining Novartis in 2010, David was a Senior Research Associate in the Department of Biochemistry at the Duke University School of Medicine where he characterized lipopolysaccharide biosynthesis, transport, and modification pathways in a variety of Gram-negative pathogens. He also led collaborations with the Gates Foundation’s Grand Challenges in Global Health Initiative and the NIH Glue Grant for LipidMAPS. David earned his M.S. and Ph.D. in Chemistry from the University of California, San Diego and B.S. in Chemistry from the University of Wisconsin, Madison.

Ram Iyer, Principal Scientist (Bacteriology), Entasis Therapeutics Inc., Waltham, MA 02451

Ram Iyer is a Principal Scientist in the Bioscience department at Entasis Therapeutics, a biotech focused on the discovery & development of novel antibiotics to treat serious Gram-negative infections. Ram holds a Ph.D. in Biology from the University of Houston, where he studied the channel properties of E. coli porins using patch-clamp electrophysiology. His post-doctoral training was on prokaryotic inner membrane transporters and bacterial pathogenesis first at HHMI, Brandeis University (Waltham, MA) and then at Tufts University School of Medicine (Boston, MA). Ram has a decade of experience in the pharmaceutical industry. Prior to joining Entasis, Ram worked at Vertex Pharmaceuticals Inc (Boston, MA) where he established systems to quantify compound entry and efflux in Gram-negative bacteria and developed genetic tools to address small molecule mechanisms-of-action (MoA) questions. At Entasis, Ram serves as the Strategic Early Exploration and Development team lead. His current interests include outer membrane porins, efflux pumps and the conception of strategies to delineate structure-porin permeation relationships.