New killing mechanism discovered in 'game-changing' antibiotic

Date:
June 5, 2020
Source:
University of Liverpool
Summary:
Scientists have taken another step forward on their quest to develop
a viable drug based on teixobactin -- a new class of potent natural
antibiotic capable of killing superbugs. New research provides
fundamental new insights into how teixobactins kill bacteria,
including the discovery of a new killing mechanism that could help
inform the design of improved teixobactin-based drugs.



FULL STORY ========================================================================== Scientists at the University of Liverpool and University of Utrecht have
taken another step forward on their quest to develop a viable drug based
on teixobactin -- a new class of potent natural antibiotic capable of
killing superbugs.


========================================================================== Research published in Nature Communications provides fundamental new
insights into how teixobactins kill bacteria, including the discovery
of a new killing mechanism that could help inform the design of improved teixobactin-based drugs.

Teixobactin was hailed as a 'game changer' when it was discovered in
2015 due to its ability kill multi-drug resistant bacterial pathogens
such as MRSA without developing resistance. If made suitable for humans,
it would mark the first new class of antibiotic drug for 30 years.

Dr Ishwar Singh, an expert in Antimicrobial Drug Discovery and Development
and Medicinal Chemistry at Liverpool's Centre of Excellence in Infectious Diseases Research, has led pioneering research over the past six years
to develop teixobactin-based viable drugs. His research team was the
first in the world to successfully create simplified synthetic forms of teixobactins which are effective in treating bacterial infections in mice.

Dr Singh explained: "We know that the therapeutic potential of simplified synthetic teixobactins is immense, and our ultimate goal is to have a
number of viable drugs from our synthetic teixobactin platform which
can be used as a last line of defence against superbugs to save lives."
In collaboration with NMR expert Professor Markus Weingarth at the
University of Utrecht, the team used high resolution solid state NMR,
and microscopy to show, for the first time, how synthetic teixobactins
bind to lipid II (an essential component of the bacterial membrane)
and kill the bacteria.

Dr Singh said: "It had been assumed that teixobactins kill the bacteria by binding to bacterial cell wall bricks such as lipid II, but never shown
until now. Our work also suggests that teixobactins kill the bacteria
by capturing lipid II in massive clusters, a new killing mechanism,
which we were excited to discover." Antimicrobial resistance (AMR)
is a grave threat to human health and prosperity. The O'Neill report, commissioned by the UK government and published in 2016, suggests that
without action AMR will cause the deaths of 10 million people a year by
2050. The development of new antibiotics is therefore a crucial area of
study for scientists around the world.

Dr Singh added: "A significant amount of work remains in the development
of teixobactins as a therapeutic antibiotic for human use. Our study
is a real step in right direction and opens the door for improving
teixobactins and moving these toward clinic.

"So far, we have demonstrated that we can make teixobactins which are
effective in treating infections from resistant bacterial pathogens and understand their binding modes in a bacterial membrane. Now we need to
expand our understanding on mode of action on a library of teixobactins
with different bacterial membranes to develop a catalogue of molecules
which have potential to become a drug for human use." Dr Singh's work
received funding support from the Department of Health and Social Care,
UK and Rosetrees Trust.


========================================================================== Story Source: Materials provided by University_of_Liverpool. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Rhythm Shukla, Joa~o Medeiros-Silva, Anish Parmar, Bram
J. A. Vermeulen,
Sanjit Das, Alessandra Lucini Paioni, Shehrazade Jekhmane, Joseph
Lorent, Alexandre M. J. J. Bonvin, Marc Baldus, Moreno Lelli,
Edwin J. A.

Veldhuizen, Eefjan Breukink, Ishwar Singh, Markus Weingarth. Mode of
action of teixobactins in cellular membranes. Nature Communications,
2020; 11 (1) DOI: 10.1038/s41467-020-16600-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200605132429.htm

--- up 19 weeks, 3 days, 2 hours, 59 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)