Study suggests metabolism influences parasite's resistance to drugs

December 01, 2020

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."
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Reference

The paper 'Glutamine metabolism modulates azole susceptibility in Trypanosoma cruzi amastigotes' can be freely accessed online at https://doi.org/10.7554/eLife.60226. Contents, including text, figures and data, are free to reuse under a CC BY 4.0 license.

*This study was originally posted on the preprint server bioRxiv, at https://www.biorxiv.org/content/10.1101/2020.06.19.161638v1.full

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Nicole Rura, Senior Media Relations Manager
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About eLife

eLife is a non-profit organisation created by funders and led by researchers. Our mission is to accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours. We work across three major areas: publishing, technology and research culture. We aim to publish work of the highest standards and importance in all areas of biology and medicine, including Microbiology and Infectious Disease, while exploring creative new ways to improve how research is assessed and published. We also invest in open-source technology innovation to modernise the infrastructure for science publishing and improve online tools for sharing, using and interacting with new results. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, the Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.

To read the latest Microbiology and Infectious Disease research published in eLife, visit https://elifesciences.org/subjects/microbiology-infectious-disease.

About Harvard T.H. Chan School of Public Health

Harvard T.H. Chan School of Public Health brings together dedicated experts from many disciplines to educate new generations of global health leaders and produce powerful ideas that improve the lives and health of people everywhere. As a community of leading scientists, educators, and students, we work together to take innovative ideas from the laboratory to people's lives - not only making scientific breakthroughs, but also working to change individual behaviours, public policies, and health care practices. Each year, more than 400 faculty members at Harvard Chan School teach 1,000-plus full-time students from around the world and train thousands more through online and executive education courses. Founded in 1913 as the Harvard-MIT School of Health Officers, the School is recognised as America's oldest professional training program in public health.

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