Antibiotic Discovery Webinar – Getting Through the Discovery Wall

2. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery Today’s Guest Moderator Antibiotic Discovery – Getting Through the Discovery Wall Joseph Thomas Associate, The Pew Charitable Trusts - Antibiotic Resistance Project Today’s Panelists Lynn Silver Silver Consulting Providing expert services in antibacterial drug discovery and preclinical development. Johannes Zuegg Program Coordinator Logistics & Chemoinformatics at CO-ADD

3. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery Adapted from Lynn L. Silver, “Challenges of Antibacterial Discovery,” Clinical Microbiology Reviews 24, no. 1. (2011): 71-109. Adapted from Lynn L. Silver, “Challenges of Antibacterial Discovery,” Clinical Microbiology Reviews 24, no. 1. (2011): 71-109 Antibiotic Discovery – Getting Through the Discovery Wall

9. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery 190, 052 compounds screened CO-ADD has screened >twice the number of any other screening program so far disclosed. McGilvray A. (2016) Nat 533, S65-7 HIT RATES [MIC ≤ 16 µg/mL] No Cytotox 0.25% for G+ve 0.07% for G-ve 0.48% for fungi Antibiotic Discovery – Getting Through the Discovery Wall

12. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery GN Barriers (simplistic view) OM CM periplasm LPS &O-Ag  OM excludes hydrophobic and hydrophilic compounds.  Penetration of hydrophilic compounds through OM is via porins  But hydrophilic and highly charged molecules entering the periplasm  penetrate the CM slowly or not at all  unless actively transported [or via PMF]  Molecules that do enter can be effluxed  What molecules can accumulate in the GN cytoplasm?

17. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery Where we need funding NIH, ENABLE CARB-X Sources: Michael J. Fox Foundation for Parkinson’s Research; FasterCures Antibiotic Discovery – Getting Through the Discovery Wall

18. Gram-positive CM Cytoplasm Gram-negative OM CM Periplasm Cytoplasm P. aeruginosa -lactams Glycopeptides Cycloserine Fosfomycin Rifampin Aminoglycosides Tetracyclines Chloramphenicol Macrolides Lincosamides Oxazolidinones Fusidic Acid Mupirocin Novobiocin Fluoroquinolones Sulfas Trimethoprim Metronidazole Daptomycin Polymyxin Antibacterial Spectrum Spectrum is largely due to permeability & efflux

19. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery Binning cytoplasmic drugs -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 0 200 400 600 800 1000 1200 1400 GN diffusion GN transported Aminoglycosides (SPU) GP only diffusion Triclosan cLogD7.4 MW

25. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery Aims from the Pew Roadmap • A better understanding of how to overcome the cellular defenses of drug-resistant Gram-negative bacteria, which cause some of the most difficult-to-treat infections. • Generation of new chemical matter designed for antibiotic discovery. • Tools and methodologies to evaluate promising alternatives to traditional antibiotic use.

27. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery Today’s Guest Moderator CONTACT US Antibiotic Discovery – Getting Through the Discovery Wall Joseph Thomas Associate, The Pew Charitable Trusts - Antibiotic Resistance Project Contact: jthomas@pewtrusts.org Today’s Panelists Lynn Silver Silver Consulting Providing expert services in antibacterial drug discovery and preclinical development. Contact: silverly@comcast.net Johannes Zuegg Program Coordinator Logistics & Chemoinformatics at CO-ADD Contact: j.zuegg@imb.uq.edu.au

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