In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica

Abstract Introduction Leishmania aethiopica (L. aethiopica) is responsible for different forms of cutaneous leishmaniasis (CL) in Ethiopia. Treatment heavily depends on limited drugs, together with drawbacks like toxicity and microbial resistance. The current research aimed to investigate in vitro g...

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Autores principales:	Markos Tadele, Solomon M. Abay, Peter Asaga, Eyasu Makonnen, Asrat Hailu
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Leishmania aethiopica Cutaneous leishmaniasis Pathogen box Therapeutics. Pharmacology RM1-950 Toxicology. Poisons RA1190-1270
Acceso en línea:	https://doaj.org/article/4ce5311b3d59402a85464c4df73eb191
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spelling	oai:doaj.org-article:4ce5311b3d59402a85464c4df73eb1912021-11-21T12:15:59ZIn vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica10.1186/s40360-021-00538-22050-6511https://doaj.org/article/4ce5311b3d59402a85464c4df73eb1912021-11-01T00:00:00Zhttps://doi.org/10.1186/s40360-021-00538-2https://doaj.org/toc/2050-6511Abstract Introduction Leishmania aethiopica (L. aethiopica) is responsible for different forms of cutaneous leishmaniasis (CL) in Ethiopia. Treatment heavily depends on limited drugs, together with drawbacks like toxicity and microbial resistance. The current research aimed to investigate in vitro growth inhibitory activity of Medicines for Malaria Ventures - Pathogen Box (MMV - PB) compounds against L. aethiopica clinical isolate. Methodology Four hundred MMV – PB compounds were screened against L. aethiopica using resazurin based colourimetric assay. Compounds with > 70% inhibition were further tested using macrophage based intracellular amastigote assay. Cytotoxic and hemolytic activity of candidate hits were assessed on THP1- cells and sheep red blood cells (RBCs), respectively. In vitro drug interaction study was also conducted for the most potent hit using the combination index method. Results At the test concentration of 1 μM, twenty-three compounds showed > 50% inhibition of promastigotes parasite growth, of which 11 compounds showed > 70% inhibition. The 50% growth inhibition (IC50) of the 11 compounds was ranged from 0.024 to 0.483 μM in anti-promastigote assay and from 0.064 to 0.899 μM in intracellular amastigote assay. Candidate compounds demonstrated good safety on sheep RBCs and THP-1 cell lines. MMV688415 demonstrated a slight hemolytic activity on sheep RBC (5.3% at 25 μM) and THP-1 cell line (CC20 = 25 μM) while MMV690102 inhibited half of THP-1 cells at 36.5 μM (selectivity index = 478). No synergistic activity was observed from the combinations of MMV690102 and amphotericin B (CI > 1), and MMV690102 and Pentamidine (CI > 1) at lower and higher combination points. Conclusion The present study identified a panel of compounds that can be used as a novel starting point for lead optimization. MMV690102 appears to be the most potent inhibitor against L. aethiopica promastigotes and amastigotes. Future works should investigate the antileishmanial mechanism of action and in vivo antileishmanial activities of identified hits.Markos TadeleSolomon M. AbayPeter AsagaEyasu MakonnenAsrat HailuBMCarticleLeishmania aethiopicaCutaneous leishmaniasisPathogen boxTherapeutics. PharmacologyRM1-950Toxicology. PoisonsRA1190-1270ENBMC Pharmacology and Toxicology, Vol 22, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Leishmania aethiopica Cutaneous leishmaniasis Pathogen box Therapeutics. Pharmacology RM1-950 Toxicology. Poisons RA1190-1270
spellingShingle	Leishmania aethiopica Cutaneous leishmaniasis Pathogen box Therapeutics. Pharmacology RM1-950 Toxicology. Poisons RA1190-1270 Markos Tadele Solomon M. Abay Peter Asaga Eyasu Makonnen Asrat Hailu In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica
description	Abstract Introduction Leishmania aethiopica (L. aethiopica) is responsible for different forms of cutaneous leishmaniasis (CL) in Ethiopia. Treatment heavily depends on limited drugs, together with drawbacks like toxicity and microbial resistance. The current research aimed to investigate in vitro growth inhibitory activity of Medicines for Malaria Ventures - Pathogen Box (MMV - PB) compounds against L. aethiopica clinical isolate. Methodology Four hundred MMV – PB compounds were screened against L. aethiopica using resazurin based colourimetric assay. Compounds with > 70% inhibition were further tested using macrophage based intracellular amastigote assay. Cytotoxic and hemolytic activity of candidate hits were assessed on THP1- cells and sheep red blood cells (RBCs), respectively. In vitro drug interaction study was also conducted for the most potent hit using the combination index method. Results At the test concentration of 1 μM, twenty-three compounds showed > 50% inhibition of promastigotes parasite growth, of which 11 compounds showed > 70% inhibition. The 50% growth inhibition (IC50) of the 11 compounds was ranged from 0.024 to 0.483 μM in anti-promastigote assay and from 0.064 to 0.899 μM in intracellular amastigote assay. Candidate compounds demonstrated good safety on sheep RBCs and THP-1 cell lines. MMV688415 demonstrated a slight hemolytic activity on sheep RBC (5.3% at 25 μM) and THP-1 cell line (CC20 = 25 μM) while MMV690102 inhibited half of THP-1 cells at 36.5 μM (selectivity index = 478). No synergistic activity was observed from the combinations of MMV690102 and amphotericin B (CI > 1), and MMV690102 and Pentamidine (CI > 1) at lower and higher combination points. Conclusion The present study identified a panel of compounds that can be used as a novel starting point for lead optimization. MMV690102 appears to be the most potent inhibitor against L. aethiopica promastigotes and amastigotes. Future works should investigate the antileishmanial mechanism of action and in vivo antileishmanial activities of identified hits.
format	article
author	Markos Tadele Solomon M. Abay Peter Asaga Eyasu Makonnen Asrat Hailu
author_facet	Markos Tadele Solomon M. Abay Peter Asaga Eyasu Makonnen Asrat Hailu
author_sort	Markos Tadele
title	In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica
title_short	In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica
title_full	In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica
title_fullStr	In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica
title_full_unstemmed	In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica
title_sort	in vitro growth inhibitory activity of medicines for malaria venture pathogen box compounds against leishmania aethiopica
publisher	BMC
publishDate	2021
url	https://doaj.org/article/4ce5311b3d59402a85464c4df73eb191
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In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopica

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