Upload
lixin-liu
View
1.051
Download
0
Embed Size (px)
Citation preview
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
“Antibiotic Discovery –
Getting Through the Discovery Wall”
Town Hall Webinar
September 20, 2017
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
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
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
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
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
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?
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Collaborating Scientists!
Antibiotic Discovery – Getting Through the Discovery Wall
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
Gram-positive
CM
Cytoplasm
Gram-negative
OM
CM
Pe
rip
lasm
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
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
cL
og
D7.4
MW
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
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.
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
Questions?
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:
Today’s Panelists
Lynn Silver Silver Consulting
Providing expert services in
antibacterial drug discovery
and preclinical development.
Contact:
Johannes Zuegg Program Coordinator
Logistics & Chemoinformatics at
CO-ADD
Contact:
Copyright © 2017 All Rights Reserved Collaborative Drug Discovery
Antibiotic Discovery – Getting Through the Discovery Wall
THANK YOU
For further contact with CDD: