Graduation Year

2018

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Global Health

Major Professor

Dennis E. Kyle, Ph.D.

Co-Major Professor

Thomas R. Unnasch, Ph.D.

Committee Member

Bill J. Baker, Ph.D.

Committee Member

Rays Jiang, Ph.D.

Keywords

Drug Discovery, Leishmania, Natural Product, Synthetic

Abstract

Leishmaniasis is a disease caused by obligate intracellular parasites of the genus Leishmania, including 20 species that are pathogenic to humans. Female sand fly is the known vector that can transmit the disease. Visceral leishmaniasis is the severe form of the disease that affects internal organs and can be fatal with inappropriate diagnosis or treatment. Leishmania donovani is the causative agent of visceral leishmaniasis. Approximately 350 million in 89 countries are at risk of infection. Around 2 million new cases are reported annually with 500,000 of these are visceral leishmaniasis. Current drug therapies are inadequate due to their toxicity, high cost, severe adverse reaction, limited availability, and the emergence of resistance. With all these limitations, the need for new drugs is urgent.

Pentavalent antimonials are the first line of treatment for leishmaniasis since the 1940s. Although amphotericin B, pentamidine and paromomycin are current drugs that treat leishmaniasis, they were discovered initially as a treatment for other pathogens. Furthermore, miltefosine the only available oral drug for leishmaniasis is an anticancer drug that found to be active against Leishmania. Therefore, we used our quantitative Leishmania donovani axenic amastigote assay and the clinically relevant infected macrophage assay to identify new antileishmanial hits from unstudied or understudied natural product sources such as mangrove endophytic fungi, Antarctic deep-sea coral, and terrestrial plants. We also used the same assays to screen synthetic compounds form multiple chemical scaffolds.

Our well-established assays led to the identification of new antileishmanial hits from unstudied natural products and the discovery of new classes of molecules from synthetic compounds that possess potent activity against Leishmania donovani. Finally, we conducted an in vivo hamster study on an active hit that revealed high efficacy against Leishmania donovani in this severe model leading to promising antileishmanial drug development.

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