TTUHSC-TTU research collaboration leads to possible drug targets for leishmaniasis

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image: TTUHSC Andrey Karamyshev, Ph.D., (left) and TTU Zemfira Karamysheva, Ph.D., investigated the molecular mechanisms responsible for producing antimony drug resistance in Leishmania parasites. Their study was published in May by Nature Communications.
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Credit: TUHSC

Leishmaniasis is a tropical disease caused by parasites known as leishmania, which are transmitted to humans and animals through the bites of over 90 species of sandflies. Considered a neglected tropical disease, leishmaniasis is found in about 88 countries located mainly in South and Central America, the Middle East and Western Asia. Up to 1 million new cases are diagnosed each year and more than 350 million people are at risk of infection. Some forms of the disease have also emerged in Mexico and Texas in recent years.

As there are very few alternatives for treating the disease, there is an urgent need to understand the resistance mechanisms associated with antimonial drugs so that more effective therapeutic options can be developed. To help address the shortage of leishmaniasis treatment options, a team of researchers led by Zemfira Karamysheva, Ph.D., of Texas Tech University (TTU) and Andrey Karamyshev, Ph.D., of Texas Tech University Health Sciences Center (TTUHSC) recently completed a study to determine the molecular mechanisms responsible for the production of antimony drug resistance in Leishmania parasites.

The research team also included first author Sneider Alexander Gutierrez Guarnizo, Ph.D., of the TTUHSC and the University of Antioquia in Medellín, Antioquia, Colombia; Elena Tikhonova, Ph.D., (TTUHSC); and Carlos Muskus, Ph.D., (University of Antioquia). Their study, “Translational reprogramming as a driver of antimony-drug resistance in Leishmania,” was published in May by Nature communications. It was also featured by the editors of the journal Highlights of Recent Research at www.nature.com/collections/jedgcgeija.

Leishmaniasis is a zoonotic disease, which means that it affects not only humans but also other animals such as dogs, horses, rodents, armadillos and many more. It can present in different forms, depending on the strain involved and the state of the host’s immune system. People with cutaneous leishmaniasis have painful skin ulcers, while people with mucocutaneous leishmaniasis develop sores and tissue damage in the mouth, lips, or mucous membranes of the nose. Visceral leishmaniasis, which is the most dangerous form of the disease, affects internal organs such as the spleen, liver and bone marrow and causes 20,000 to 30,000 deaths annually.

For the past 70 years, chemotherapy with pentavalent antimonials such as sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime) has been the primary regimen used to treat leishmaniasis. However, the efficacy of antimonials steadily declines over time, and disease resistance to pentavalent antimonials is markedly increased.

Karamyshev said the development of drug resistance in leishmaniasis is similar to that in cancer patients who develop resistance to chemotherapy. When treated with chemotherapy drugs, leishmania parasites, like cancer cells, also develop resistance. However, resistance in leishmaniasis differs from that in cancer because it lacks transcriptional regulation (the process cells use to control the conversion of DNA to RNA) and is primarily regulated by protein synthesis. Protein production contributes to the development of drug resistance.

“That was the goal of the study: to find out how regulation of protein synthesis contributes to the development of antimony resistance,” Karamyshev said. “Basically, how do changes in protein production contribute to drug resistance?”

Karamysheva said the team conducted two types of comparisons using a group of drug-sensitive Leishmania parasites and a group of drug-resistant Leishmania parasites that were developed by gradually increasing the drug concentration over a six-month period.

“We compared how protein production in resistant parasites differs from that in susceptible parasites,” Karamysheva said. “We also compared the drug-resistant parasite without the drug to the drug-resistant parasite with the drug to see the response to the drug.”

Karamysheva said the most interesting finding was that even without the drug, drug-resistant parasites have two totally different protein production profiles compared to susceptible parasites.

“Many, many proteins are made differently in the drug-resistant parasite, so we have basically observed global reprogramming of protein production; we think this is a preemptive adaptation,” Karamysheva explained. “That’s why we were very interested in understanding how that resistance develops in those parasites. Specifically, we wanted to know the role of translational control (protein production) in the development of resistance to drugs in leishmania”.

Preventive adaptations – specific changes that occur during the development of drug resistance when the parasite may acquire multiple adaptations – provide parasites with the ability to respond instantly and effectively to an anticipated threat. These adaptations remain in place when the drug is absent and begin to work to support parasite survival when drug exposure occurs. This means that even in the absence of the drug the Leishmania parasite remains ready to see and react to the drug. Furthermore, the many protein changes observed in the study (2,431) provide the Leishmania parasite with some preventive adaptations that help it locate the drug more efficiently. In contrast, the team observed a very small number of proteins (189) that change their expression in drug-resistant parasites that were treated with the drug.

Karamyshev said that one of the main points developed through the leishmania comparisons is that preemptively adapted parasites can respond very effectively when they see the drug and do not need to make significant adaptations to respond to the drug’s presence. Comparisons have also shown that protein helps contribute to the development of drug resistance.

“There are multiple mechanisms that can contribute to drug resistance, such as how the parasite fights oxidative stress or how effectively the parasite can pour the drug out of the cell,” Karamysheva added. “We want to see the whole picture of how it’s happening.”

The identification of 189 differentially expressed proteins in the drug-treated drug-resistant strain provides the research team with 189 potential drug targets for the treatment of leishmaniasis. In future research, they will evaluate the function of each of the 189 proteins in relation to drug resistance. They will also use a process known as drug repurposing to look for ways to overcome drug resistance. The trial will involve testing drugs that have previously been approved by the FDA because they target certain human genes. Similar genes may also be present in leishmania, and Karamyshev said the team has indeed identified many of these genes.

“We basically have the genes that can contribute to drug resistance, and we have these FDA-approved drugs that could potentially target these genes and be repurposed to treat leishmaniasis,” Karamyshev said. “It’s not part of this paper, but this study can serve as a basis for finding possible drugs that can target proteins that have been specifically expressed or synthesized against us. And now we know what those proteins are.”

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