Title

Bicyclic Lactams have leishmanicidal activity against Leishmania major, the agent of Human Cutaneous Leishmaniasis

Document Type

Oral Presentation

Event Website

https://source2022.sched.com/

Start Date

18-5-2022

End Date

18-5-2022

Keywords

Leishmaniasis, parasite, drug discovery

Abstract

Leishmaniasis is an infectious disease caused by the parasitic protozoan Leishmania. Present in 88 countries, with 350 million people at risk and roughly 12 million patients, Leishmaniasis is endemic in tropical and Mediterranean areas where the female sandfly vector thrives. There are three clinical manifestations of the disease: cutaneous, mucocutaneous, and visceral leishmaniasis, also referred to as Kala-Azar. Leishmania major, the focus of this drug discovery project, manifests in humans as cutaneous leishmaniasis, a disease characteristic of its skin lesions. Amphotericin B (Amp B) is the only FDA approved treatment for leishmaniasis in the US, but is toxic to patients. Consequently, there is an urgent need for new compounds that are active against Leishmania, non-toxic or less toxic, and affordable. In my contribution to this ongoing drug discovery project, I worked to identify organic compounds that are active against Leishmania parasites. To evaluate the anti-Leishmanial activities of bicyclic lactam compounds, I preformed in vitro assays using the dye Alamar Blue to indicate cell viability. Amp B and dimethyl sulfoxide served as experimental controls. At a concentration of 100 µg/mL, eighty-four total compounds were screened. Twelve compounds were identified to have leishmanicidal activity, with an additional eight compounds that were semi-active. By performing dilution curve analyses, I found that the lowest concentration at which compounds were still active was 25 µg/mL. Using flow cytometry, the candidate compounds were analyzed against mammalian splenocytes to indicate cytotoxicity. A dual-parameter stain for apoptosis and necrosis was performed, however, preliminary findings on cytotoxicity were inconclusive.

Faculty Mentor(s)

Blaise Dondji

Department/Program

Biological Sciences

Additional Mentoring Department

Biological Sciences

Streaming Media

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Bicyclic Lactams have leishmanicidal activity against Leishmania major, the agent of Human Cutaneous Leishmaniasis

Leishmaniasis is an infectious disease caused by the parasitic protozoan Leishmania. Present in 88 countries, with 350 million people at risk and roughly 12 million patients, Leishmaniasis is endemic in tropical and Mediterranean areas where the female sandfly vector thrives. There are three clinical manifestations of the disease: cutaneous, mucocutaneous, and visceral leishmaniasis, also referred to as Kala-Azar. Leishmania major, the focus of this drug discovery project, manifests in humans as cutaneous leishmaniasis, a disease characteristic of its skin lesions. Amphotericin B (Amp B) is the only FDA approved treatment for leishmaniasis in the US, but is toxic to patients. Consequently, there is an urgent need for new compounds that are active against Leishmania, non-toxic or less toxic, and affordable. In my contribution to this ongoing drug discovery project, I worked to identify organic compounds that are active against Leishmania parasites. To evaluate the anti-Leishmanial activities of bicyclic lactam compounds, I preformed in vitro assays using the dye Alamar Blue to indicate cell viability. Amp B and dimethyl sulfoxide served as experimental controls. At a concentration of 100 µg/mL, eighty-four total compounds were screened. Twelve compounds were identified to have leishmanicidal activity, with an additional eight compounds that were semi-active. By performing dilution curve analyses, I found that the lowest concentration at which compounds were still active was 25 µg/mL. Using flow cytometry, the candidate compounds were analyzed against mammalian splenocytes to indicate cytotoxicity. A dual-parameter stain for apoptosis and necrosis was performed, however, preliminary findings on cytotoxicity were inconclusive.

https://digitalcommons.cwu.edu/source/2022/COTS/65