A new way to disarm antibiotic resistance in deadly bacteria

Date:
February 22, 2022
Source:
University of Texas at Austin
Summary:
Scientists think they may have uncovered a whole new approach
to fighting antibiotic-resistant bacteria, which, if successful,
would help address a health crisis responsible for more deaths every
year than either AIDS or malaria. A team of researchers found a new
way to impair antibiotic resistance in bacteria that cause human
disease. The team made the bacteria vulnerable again to antibiotics
by inhibiting a particular protein that drives the formation of
resistance capabilities within the bacteria, called DsbA.



FULL STORY ========================================================================== Scientists think they may have uncovered a whole new approach to fighting antibiotic-resistant bacteria, which, if successful, would help address
a health crisis responsible for more deaths every year than either AIDS
or malaria.


==========================================================================
A team of researchers led by Despoina Mavridou of The University of
Texas at Austin found a new way to impair antibiotic resistance in
bacteria that cause human disease, including E. coli, K. pneumoniae and
P. aeruginosa, which are responsible for the majority of harm caused
by resistant infections. The team made the bacteria vulnerable again to antibiotics by inhibiting a particular protein that drives the formation
of resistance capabilities within the bacteria.

"It's a completely new way of thinking about targeting resistance,"
said Mavridou, an assistant professor of molecular biosciences.

Bacteria are becoming increasingly resistant to existing antibiotics,
and researchers have struggled to identify new bacteria-fighting drugs,
leaving the world vulnerable to deadly superbugs. A January study in
The Lancet by another team found antimicrobial resistance to be the
direct cause of at least 1.27 million deaths globally in 2019, making antibiotic resistance one of the world's leading causes of death.

Antibiotic resistant bacteria have a host of different proteins in
their arsenals that neutralize antibiotics. To function properly, these resistance proteins must be folded into the right shapes. The researchers discovered that yet another protein, called DsbA, helps fold resistance proteins into those shapes.

For their proof-of-concept study, which was recently published in the
journal eLife,Mavridou and her fellow scientists inhibited DsbA using
chemicals that cannot be used directly in human patients. The team plans
now to work on developing inhibitors that can achieve the same outcome
and be safely used in humans.



========================================================================== "Other approaches focus on inhibiting resistance proteins, but nobody
had thought to try and prevent their formation in the first place,"
Mavridou said.

Their goal is to combine a DsbA inhibitor with existing antibiotics
to restore the drugs' ability to kill bacteria. Because it targets the machinery that helps assemble antibiotic-resistance proteins in dangerous bacteria, the approach would render several types of proteins critical
for resistance ineffective by preventing their ability to fold or create disulfide bonds.

"Since the discovery of new antibiotics is challenging, it is crucial
to develop ways to prolong the lifespan of existing antimicrobials,"
said Christopher Furniss, one of the lead authors of this study at
Imperial College London. "Our findings show that by targeting disulfide
bond formation and protein folding, it is possible to reverse antibiotic resistance across several major pathogens and resistance mechanisms. This
means that the development of clinically useful DsbA inhibitors in
the future could offer a new way to treat resistant infections using
currently available antibiotics." DsbA is mostly a house-keeping protein
in bacteria that promotes protein stability and folding. Before this
study, scientists already knew that DsbA is also involved in a range of functions in pathogens, such as helping build toxins that attack host
cells, or assisting with the assembly of needle-like systems that can
deliver these toxins into human cells and cause disease. But Mavridou,
who studied DsbA for many years, suspected that it might also play
an important role in the folding of proteins that help bacteria resist antibiotics. She started investigating this possibility while at Imperial College London, before joining the UT Austin faculty in 2020.

"We reasoned that if DsbA is required for the folding of resistance
proteins, preventing it from working would indirectly inhibit their
function," said Nikol Kaderabkova, a postdoctoral researcher at UT
Austin and the second lead author of the study. In continuing work on
this system, Kade?a'bkova' is driving the current effort to discover
DsbA inhibitors that would be safe in humans.

The other researchers involved in the study are based at Imperial College London (U.K.), Universidad de Sevilla (Spain), Brunel University London
(U.K.), University of Birmingham (U.K.), Paris-Sud University (France),
and Universite' de Neucha^tel (Switzerland).

This research was supported in part by the National Institute of Allergy
and Infectious Diseases of the National Institutes of Health.

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


========================================================================== Journal Reference:
1. Nikol Kaderabkova, R Christopher D Furniss, Declan Barker, Patricia
Bernal, Evgenia Maslova, Amanda AA Antwi, Helen E McNeil, Hannah
L Pugh, Laurent Dortet, Jessica MA Blair, Gerald Larrouy-Maumus,
Ronan R McCarthy, Diego Gonzalez, Despoina AI Mavridou. Breaking
antimicrobial resistance by disrupting extracytoplasmic protein
folding. eLife, 2022; 11 DOI: 10.7554/eLife.57974 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220222135331.htm

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