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Printable Handouts
Navigable Slide Index
- Introduction
- Learning objectives
- The urgent need (1)
- The urgent need (2)
- Challenges - cost
- Antibiotic discovery of the past
- Antibiotic discovery of the present
- TB antibiotic drug discovery pipeline – a convenient case study
- Target ID and validation (1)
- Finding the mechanism of action – a critical step
- The imidazo[1,2-a]pyridines
- Resistant mutants
- Whole genome sequencing (WGS) results
- Validation of QcrB Target
- Target ID and validation (2)
- EchA6: target of THPPs
- Role of Mt-MmpL3, TMM transport and diverse chemical scaffolds target MmpL3
- A different approach: quantitative chemical proteomics
- Essentiality and conditional depletion of echA6 gene in M. bovis BCG
- Synthesis of FAMEs and MAMEs in the presence of MmpL3 inhibitors (1)
- Synthesis of FAMEs and MAMEs in the presence of MmpL3 inhibitors (2)
- Whole cell target engagement established through overexpression
- FAMEs and MAMEs synthesis using pVV16 and pVV16-echA6 cultures
- Lipid catabolic pathway
- Fluorescence binding assays of MTb-EchA6 with acyl-CoAs
- Mtb-EchA6 complexed with either C20-CoA or GSK951A
- Protein-protein interaction screen using the bacterial two-hybrid system
- In vivo validation
- Changing the dogma
- The best thing I ever did…
- Conclusions
Topics Covered
- Why we need new antibiotics
- Different approaches to drug discovery
- Phenotypic drug discovery
- Limitations of phenotypic drug discovery
Talk Citation
Cox, J. (2022, August 30). Strengths and limitations of phenotypic drug discovery [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 6, 2024, from https://doi.org/10.69645/JMJD3728.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Jonathan Cox has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
A selection of talks on Methods
Transcript
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0:00
In this talk, I'm going
to discuss the strengths
and limitations of
phenotypic drug discovery.
I'm Dr. Jonathan Cox,
Senior Lecturer in Microbiology
at Aston University.
0:14
In this talk, I'm going to
cover a few key things.
The first of which is,
why we need new antibiotics,
what I like to call
'The Urgent Need'.
I'm then going to discuss
different approaches to
antibiotic discovery.
Then I'm going to run through
a couple of case studies.
The first of which will cover
phenotypic drug discovery.
The second one will
clearly demonstrate the
limitations of phenotypic
drug discovery.
0:44
Why do we need antibiotics?
This figure from the O'Neill review
on antimicrobial resistance,
exemplifies the importance
of finding new antibiotics.
Currently, 700,000 people a year
die from antibiotic-resistant
infections.
That number is
estimated to rise to
10 million people by 2050
if we do nothing about it.
Antibiotic resistance
could overtake cancer
as the leading cause of
death within our lifetime.
This is why it's imperative
we discover new antibiotics.
1:26
What antibiotics
do we really need?
Well, antibiotics are
powerful selective poisons.
They kill bacteria, but
they don't kill us.
They're a magic
bullet if you like.
We need antibiotics that
can work like this,
but that are able to overcome
existing mechanisms of
antibiotic resistance.
We don't want to create
a selection pressure
for more resistance ideally.
We need highly regulated
and restricted use
of these new antibiotics
and/or we want to
easily modify these
antibiotics to produce
second and third line drugs
should antibiotic resistance
to that class emerge.
Importantly, they need
to be cheap to produce.
They need a broad
spectrum of activity.
They need to be useful
to treat the full range
of bacterial
pathogens, the A to Z,
from Acinetobacter
through to Yersinia.
I couldn't think
of a bacterial Z.
The 2017 estimate puts
the cost of developing