Feeding routes
NMR spectroscopy has provided researchers with insights into how parasitic organisms exploit nutrients provided by the host organism. The work could open up a new approach to finding unique drug targets and in the present study, specifically against the tropical parasite Leishmania.
Leishmania is trypanosomatid protozoon and is responsible for the tropical disease leishmaniasis, spreading through infection by sandfly bite. Currently it affects 12 million people in 88 countries causing everything from skin conditions to organ damage. It kills 50,000 people each year, predominantly in the developing world. There are few drugs for treating the disease including pentavalent antimonial compounds, such as sodium stibogluconate and meglumine antimoniate, but resistance to these drugs is widespread in many parts of the world. There are alternatives, including amphotericin B and the less costly and safer paromomycin, which is being advocated as an orphan drug in India. Vaccines against this complex parasite are of limited use.
However, a team led by Malcolm McConville from the Bio21 Institute, at the University of Melbourne, Australia, hope that their research will lead the way to new targets for novel drugs that might, for a time, side-step resistance. They have developed a new analytical method that could be used to study many infectious agents including Leishmania mexicana and other parasites and bacteria. The technique uses NMR spectroscopy and gas chromatography-mass spectrometry to identify which metabolic pathways are essential for the parasite's survival and which are non-essential, pinpointing the specific nutrients at the molecular level.
Vectors and hosts
The nutritional niche within which the parasite exists in its vector, the sandfly, and its mammalian hosts is complex and poorly understood. Now, the team has demonstrated that specifically inhibiting the mitochondrial enzyme aconitase with sodium fluoroacetate results in rapid depletion of intracellular glutamate pools and growth arrest because the parasite can no longer make this essential nutrient. "Growth can be restored by addition of very high concentrations of glutamate, but these levels are unlikely to occur in the animal host," McConville told SpectroscopyNOW. "These findings suggest that glycosomal and mitochondrial metabolism in Leishmania promastigotes is tightly coupled and that, in contrast to the situation in some other trypanosomatid parasites, the TCA cycle has crucial anabolic functions," the team says. The promastigotes are the extracellular form of the parasite which lives in the gut of sandflies.
"This a very significant breakthrough in this field because the more we know about these dangerous pathogens and how they live, the better we can fight them with new, effective drugs," explains McConville. He adds that "Current anti-parasitic drugs have enormous side effects as they don't target specific pathogen metabolic pathways. We now have a greater understanding of Leishmania and can develop specific drugs with minimal side effects."
Labelled insights
The team used carbon-13 isotopic labelling of glucose to track the metabolic path followed by the sugar fed to the parasite. Revealing which metabolic pathways are essential to Leishmania's survival offers new targets for blocking the enzymes and or receptors critical to those pathways and so kill the parasite.
The techniques developed in this research by the Australian team offers new hope of studying other pathogens. The work highlights how useful stable isotope tracing and metabolomic approaches can be in identifying stage- and species-specific differences in the metabolic networks of such parasites, the team concludes.
The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.
|
