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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| Format: | Article |
| Language: | English |
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BMC
2021-11-01
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| Series: | BMC Pharmacology and Toxicology |
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| Online Access: | https://doi.org/10.1186/s40360-021-00538-2 |
| _version_ | 1818932817188356096 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T04:38:31Z |
| format | Article |
| id | doaj.art-4ce5311b3d59402a85464c4df73eb191 |
| institution | Directory Open Access Journal |
| issn | 2050-6511 |
| language | English |
| last_indexed | 2024-12-20T04:38:31Z |
| publishDate | 2021-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Pharmacology and Toxicology |
| spelling | doaj.art-4ce5311b3d59402a85464c4df73eb1912022-12-21T19:53:12ZengBMCBMC Pharmacology and Toxicology2050-65112021-11-0122111010.1186/s40360-021-00538-2In vitro growth inhibitory activity of Medicines for Malaria Venture pathogen box compounds against Leishmania aethiopicaMarkos Tadele0Solomon M. Abay1Peter Asaga2Eyasu Makonnen3Asrat Hailu4Animal Health Research Program, Ethiopian Institute of Agricultural ResearchDepartment of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa UniversityInstitute of Human Virology, University Freiburg Medical CentreDepartment of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa UniversityCenter for Innovative Drug Development and Therapeutic Trials for Africa (CDT Africa), College of Health Sciences, Addis Ababa UniversityAbstract 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.https://doi.org/10.1186/s40360-021-00538-2Leishmania aethiopicaCutaneous leishmaniasisPathogen box |
| spellingShingle | 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 BMC Pharmacology and Toxicology Leishmania aethiopica Cutaneous leishmaniasis Pathogen box |
| title | 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_short | 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 |
| topic | Leishmania aethiopica Cutaneous leishmaniasis Pathogen box |
| url | https://doi.org/10.1186/s40360-021-00538-2 |
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