Metabolism influences parasite's resistance to drugs

Date:
December 1, 2020
Source:
eLife
Summary:
New insight on how a parasite can resist current therapies has
just been published.



FULL STORY ==========================================================================
New insight on how a parasite can resist current therapies has been
published today in the open-access eLife journal.


==========================================================================
The study in cultures of human cells infected with Trypanosoma
cruzi(T. cruzi), the parasite that causes Chagas disease, suggests that
its metabolic state influences the effectiveness of azole drugs that
inhibit its growth. These findings could be useful for the development
of more effective antimicrobial treatments.

Chagas disease, also known as American trypanosomiasis, can cause a
sudden, brief (acute) illness, or it may be a long-lasting (chronic)
condition. Around six to seven million people worldwide are estimated
to be infected with the T.

cruzi pathogen that causes the disease, according to the World Health Organization. Symptoms can range from mild to severe, but do not often
appear until the chronic stage of disease.

"The goal for the treatment of Chagas and other infectious diseases is
to eliminate the pathogen from the infected host," explains first author
Peter Dumoulin, Postdoctoral Fellow at senior author Barbara Burleigh's
lab, Harvard T. H. Chan School of Public Health, Boston, US. "There are
a few ways in which pathogens can survive antimicrobial treatment. One
of the less explored options is the impact of their metabolic and
environmental diversity (or heterogeneity) on the effectiveness of a
given treatment, and we wanted to find out if these factors play a role
in T. cruzi's drug resistance." There is an intracellular stage in the
T. cruzi life-cycle where they become amastigotes -- replicative forms of
the parasite that persist in the infected host. The team's work revealed
that the sensitivity of amastigotes to azole drugs increases significantly
in the presence of certain concentrations of the amino acid glutamine, independent of the parasite's growth rate.

Further metabolic labelling and inhibitor studies showed that T. cruzi's glutamine metabolism leads to the enhanced production of steroid alcohols (sterols), along with an accompanying accumulation of non-standard sterols
and toxicity to the parasite in the presence of azoles. These findings
suggest that metabolic heterogeneity in the parasite-host interaction
may contribute to the failure of some drugs to achieve sterile cure, demonstrating a novel link between metabolism and drug efficacy.

"Our work provides further evidence that the metabolic state of
a microorganism is important for determining its susceptibility to antimicrobials, and lays the groundwork for further studies," concludes Burleigh, Professor of Immunology and Infectious Diseases at Harvard
Chan School. "Gaining a better understanding of metabolism in T. cruzi
and other parasites, and why current drug candidates can fail to treat infection, could lead to more effective therapies for Chagas disease
and other infections."

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


========================================================================== Journal Reference:
1. Peter C Dumoulin, Joshua Vollrath, Sheena Shah Tomko, Jennifer
X Wang,
Barbara Burleigh. Glutamine metabolism modulates azole
susceptibility in Trypanosoma cruzi amastigotes. eLife, 2020;
9 DOI: 10.7554/eLife.60226 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/12/201201144054.htm

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