academic drug discovery from the perspective of a bacterial geneticist
TRANSCRIPT
Rob AbramovitchDept. Microbiology and Molecular Genetics, Michigan State University
Academic drug discovery from the perspective of a bacterial geneticist
Genetics driven approach to discovering new antibiotics
Wild Type IdentifyMutant
Characterize Mutant
Genetic discovery pipeline
Identify inhibitors of the protein of interest
Test Activity in Cells
Identify and optimize lead compound
Drug discovery pipeline
Pitfalls: -- Long lead time until drug discovery work begins-- Targets with redundancy are difficult to discover with genetic
approaches-- Target pathway is recalcitrant to drug development
Chemical biology approach to discovering new antibiotics
Test Activity in Cells
Identify and optimize lead compound
Characterize compound treated cells
Identify mutants resistant to compound
Drug discovery pipeline
Chemical Biology pipeline
Chemical treated cell is analogous to mutant allele
Advantages: -- Translation-driven, while still generating basic research discoveries-- Identify targets inaccessible to standard genetic
approaches (redundant genes)
Acidic pH M. tuberculosis biosensor
Abramovitch et al., Mol. Micro. 2011
Acidic pH 5.7 Neutral pH 7.0
Acidic pH-sensing is essential for pathogenesis
Screening 890,000 compounds for inhibitors of biosensor florescence
42,420 compounds
Ethoxzolamide inhibits pH-dependent biosensor fluorescence in macrophages and attenuates virulence
Johnson et al., 2015, Antimicrobial Agents and Chemotherapy, doi: 10.1128/AAC.00719-15
AppliedBasic
Academic Drug Discovery
1. New knowledge2. Innovation3. Train new scientists
1. Impact human health2. Economic development3. Forging new relationships4. New funding opportunities
AcknowledgementsAbramovitch Lab:Jake BakerChris ColvinGarry CoulsonBenjamin JohnsonDavid NeedleJaviera OrtizHuiqing ZhengRobert FillingerBoitshoko MolefhiHinako Terauchi
Harvard Medical School:Su ChiangDoug Flood, Jen Smith
University of Notre Dame:Patty ChampionFelix Mba Medie
Vertex Pharmaceuticals:Christine MemmottChristopher Locher
Funding:Bill & Melinda Gates Foundation (OPP1059227)Bill & Melinda Gates Foundation (OPP1119065)NIH NIAID Great Lakes RCE (U54AI057153) NIH NIAID (R21AI105867) MI Innov. & Entrepreneurship (2014-00199)MSU and AgBioResearch start up fundingJean P. Schultz Endowed Biomedical Research Fund at the MSU College of Human Medicine.