antibiotic discovery webinar – getting through the discovery wall

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:

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

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