Slides from CDD's Q3 webinar where Dr. Lynn Silver and Dr. Johannes Zuegg (CO-ADD) tackle the increasingly difficult task of finding new, effective antibiotics. Moderated by Joe Thomas, The Pew Charitable Trusts.

1. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
“Antibiotic Discovery –
Getting Through the Discovery Wall”
Town Hall Webinar
September 20, 2017

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

4. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

5. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

6. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

7. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

8. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
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

10. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

11. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
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?

13. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Antibiotic Discovery – Getting Through the Discovery Wall

14. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

15. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery WallAntibiotic Discovery – Getting Through the Discovery Wall

16. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Collaborating Scientists!
Antibiotic Discovery – Getting Through the Discovery Wall

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

20. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

21. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

22. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

23. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

24. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall

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.

26. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Questions?

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

28. Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
THANK YOU
For further contact with CDD:
info@collaborativedrug.com