academic drug discovery from the perspective of a bacterial geneticist

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.