Study reveals how drug resistant bacteria

secrete toxins, suggesting targets to reduce

virulence

February 13 2023

Credit: Unsplash/CC0 Public Domain

Antimicrobial resistance represents one of the top 10 global public

health threats according to the World Health Organization, and scientists

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have been scrambling to find new tools to cure the most deadly drug-
resistant infections.

Research led by a University of Maryland scientist in collaboration with

the National Institute of Allergy and Infectious Diseases suggests that
reducing virulence in drug resistant infections rather than trying to kill
bacteria outright may offer an alternative approach to treatment.

Their study revealed how two proteins enable the methicillin-resistant

Staphylococcus aureus (MRSA) bacterium to secrete the toxins that
make people sick. The research suggests that therapies targeting these
two proteins could disable MRSA, making it less deadly and possibly
even harmless. Such an approach would also reduce the risk of
promoting antibiotic resistance.

The paper, which was published on February 13, 2023, in the

Proceedings of the National Academy of Science suggests that similar
mechanisms may exist in other bacteria, pointing to the potential for a
new approach to treating other bacterial infections.

"We were looking for an alternative way of approaching MRSA," said

Seth Dickey, an assistant professor in the UMD Department of
Veterinary Medicine and lead author of the study. "We were interested
in understanding how the bacterium causes disease to see if we could
interfere directly with the virulence factors that the bug produces. If we
can disarm it, then we may not have to worry about it evading
antimicrobial agents."

Antimicrobial resistance develops when a drug treatment knocks down

some, but not all of the bacterial cells. The bacteria that remains tends to
have some natural resistance, so if they have a chance to recolonize, the
next infection will be stronger in the face of antibiotics. This
unintentional selective breeding has led to super-bugs like MRSA and

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multi-drug resistant tuberculosis.

An approach to treating infection that makes it less harmful without

killing it, could eliminate the potential for such selective breeding. In
MRSA, that effort has been hindered by the fact that the bacterium
makes several types of toxins in abundance. Understanding each
mechanism and shutting it down is tremendously challenging. So, Dickey
and his colleagues decided not to look at how the cells produce toxins,
but how they secrete those toxins into their host.

Previous work by Dickey and other teams found that two proteins serve
as ferries to transport the molecules of toxin across the bacterial cell
membrane to the outside environment. But it was unclear why there were
two transporter proteins and how they functioned. Without this
understanding, scientists cannot develop therapies to prevent the
secretion of toxins.

To understand the mechanism at play, Dickey and his team removed

each type of transporter through genetic engineering and observed how
MRSA cells secreted toxins. They discovered that one transporter
protein collects hydrophilic, or water-loving, toxins floating in the cell's
cytoplasm and shuttles them through the cell membrane. When that
transporter was absent, hydrophilic toxins continued to build up inside
the MRSA cells where they are harmless to both MRSA and any
potential host.

When the team removed the second transporter protein, hydrophobic, or

water repulsed, toxins built up in the cell. This is significant, because
these toxins tend to move on their own out of the watery cytoplasm and
lodge themselves in the more oily cell membrane. And that's where
MRSA toxins do their damage, to host cells and to MRSA cells. So,
without the second transporter protein, MRSA cells are damaged by
their own hydrophobic toxins.

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 This suggests that future therapeutics targeting one transporter could
reduce virulence, and therapeutics targeting the second transporter could
reduce virulence while also having an antibiotic effect.

The study's findings have implications beyond MRSA. When the

researchers looked at the genomes of a variety of other bacteria, they
found that many have genes for producing a dual transport protein
system similar to the one they found in MRSA.

More information: Dickey, Seth W. et al, Two transporters cooperate

to secrete amphipathic peptides from the cytoplasmic and membranous
milieus, Proceedings of the National Academy of Sciences (2023). DOI:
10.1073/pnas.2211689120. doi.org/10.1073/pnas.2211689120

Provided by University of Maryland

Citation: Study reveals how drug resistant bacteria secrete toxins, suggesting targets to reduce
virulence (2023, February 13) retrieved 21 February 2023 from
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