Browsing by Author "Mbye, H."
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Item Stepwise in vitro screening of MMV pathogen box compounds against Plasmodium falciparum to identify potent antimalarial candidates(International Journal for Parasitology: Drugs and Drug Resistance, 2023) Mbye, H.; Bojang, F.; Jaiteh, F.K.; et al.Development of resistance to deployed antimalarial drugs is inevitable and needs prompt and continuous discovery of novel candidate drugs. Therefore, the antimalarial activity of 125 compounds from the Medicine for Malaria Ventures (MMV) pathogen box was determined. Combining standard IC50 and normalised growth rate inhibition (GR50) analyses, we found 16 and 22 compounds had higher potencies than CQ respectively. Seven compounds with relatively high potencies (low GR50 and IC50) against P. falciparum 3D7 were further analysed. Three of these were tested on 10 natural P. falciparum isolates from The Gambia using our newly developed parasite survival rate assay (PSRA). According to the IC50, GR50 and PSRA analyses, compound MMV667494 was most potent and highly cytotoxic to parasites. MMV010576 was slow acting but more potent than dihydroartemisinin (DHA) 72 h after exposure. MMV634140 was potent against the laboratory-adapted 3D7 isolate, but 4 out of 10 natural Gambian isolates survived and replicated slowly despite 72 h of exposure to the compound, suggesting potential drug tolerance and risk of resistance development. These results emphasise the usefulness of in vitro testing as a starting point for drug discovery. Improved approaches to data analyses and the use of natural isolates will facilitate the prioritisation of compounds for further clinical development.Item Stepwise in vitro screening of MMV pathogen box compounds against Plasmodium falciparum to identify potent antimalarial candidates(International Journal for Parasitology: Drugs and Drug Resistance, 2023) Mbye, H.; Bojang, F.; Jaiteh, F.K.; et al.Development of resistance to deployed antimalarial drugs is inevitable and needs prompt and continuous dis covery of novel candidate drugs. Therefore, the antimalarial activity of 125 compounds from the Medicine for Malaria Ventures (MMV) pathogen box was determined. Combining standard IC50 and normalised growth rate inhibition (GR50) analyses, we found 16 and 22 compounds had higher potencies than CQ respectively. Seven compounds with relatively high potencies (low GR50 and IC50) against P. falciparum 3D7 were further analysed. Three of these were tested on 10 natural P. falciparum isolates from The Gambia using our newly developed parasite survival rate assay (PSRA). According to the IC50, GR50 and PSRA analyses, compound MMV667494 was most potent and highly cytotoxic to parasites. MMV010576 was slow acting but more potent than dihydroartemisinin (DHA) 72 h after exposure. MMV634140 was potent against the laboratory-adapted 3D7 isolate, but 4 out of 10 natural Gambian isolates survived and replicated slowly despite 72 h of exposure to the compound, suggesting potential drug tolerance and risk of resistance development. These results emphasise the usefulness of in vitro testing as a starting point for drug discovery. Improved approaches to data analyses and the use of natural isolates will facilitate the prioritisation of compounds for further clinical development.Item Stepwise in vitro screening of MMV pathogen box compounds against Plasmodium falciparum to identify potent antimalarial candidates(Elsevier Ltd, 2023) Mbye, H.; Bojang, F.; Amambua-Ngwa, A.; et al.ABSTRACT Development of resistance to deployed antimalarial drugs is inevitable and needs prompt and continuous dis covery of novel candidate drugs. Therefore, the antimalarial activity of 125 compounds from the Medicine for Malaria Ventures (MMV) pathogen box was determined. Combining standard IC50 and normalised growth rate inhibition (GR50) analyses, we found 16 and 22 compounds had higher potencies than CQ respectively. Seven compounds with relatively high potencies (low GR50 and IC50) against P. falciparum 3D7 were further analysed. Three of these were tested on 10 natural P. falciparum isolates from The Gambia using our newly developed parasite survival rate assay (PSRA). According to the IC50, GR50 and PSRA analyses, compound MMV667494 was most potent and highly cytotoxic to parasites. MMV010576 was slow acting but more potent than dihydroartemisinin (DHA) 72 h after exposure. MMV634140 was potent against the laboratory-adapted 3D7 isolate, but 4 out of 10 natural Gambian isolates survived and replicated slowly despite 72 h of exposure to the compound, suggesting potential drug tolerance and risk of resistance development. These results emphasise the usefulness of in vitro testing as a starting point for drug discovery. Improved approaches to data analyses and the use of natural isolates will facilitate the prioritisation of compounds for further clinical developmentItem Tolerance Of Plasmodium Falciparum To Artemetherlumefantrine In The Gambia(University Of Ghana, 2020-12) Mbye, H.Antimalarial drug resistance contributes significantly to obstacles in reducing the global burden of malaria especially in sub-Saharan Africa (sSA) where the disease is most prevalent. Resistance to artemisinin-based combination therapies (ACTs), the only recommended frontline drugs for the treatment of uncomplicated malaria is now widespread in South East Asia (SEA). However, ACTs remain efficacious in sSA though in vivo delayed parasite clearance and in vitro reduced susceptibility to both components of the drug has been reported. Resistance to ACTs is therefore anticipated especially with its sustained use in endemic regions and the recent report of the emergence of de novo Pfk13 mutation that is now spreading in Rwanda. In The Gambia where artemether-lumefantrine (AL) is the first-line drug used for over 10 years, a steady increase in parasite tolerance to lumefantrine (LUM) was observed over a period of 4 years which strongly correlated with reported directional selection on a cysteine desulfarase gene (Pfnfs1). These findings are concerning and require continuous drug surveillance to track spontaneous development of AL resistant parasites and determine pathways to resistance development. This study therefore sought to investigate the prevalence and mechanisms of parasite tolerance to AL in The Gambia. A novel ex vivo drug susceptibility assay suitable to simultaneously assess parasite responses to both drugs used in AL was developed and used to assess drug susceptibility profiles of circulating parasites in western Gambia. This assay was then used to confirm identified potent compounds from the Medicines for Malaria Venture pathogen box effective against the erythrocytic stages of the parasite for future development into new antimalarial drugs. The prevalence of known drug resistance markers was assessed and novel markers that could be associated with drug resistance identified using both regression analysis and GWAS approach. Finally, CRISPR-Cas9 genome editing was used to functionally validate Pfnfs1 for its involvement in LUM tolerance using gene editing approaches. Antimalarial drug resistance contributes significantly to obstacles in reducing the global burden of malaria especially in sub-Saharan Africa (sSA) where the disease is most prevalent. Resistance to artemisinin-based combination therapies (ACTs), the only recommended frontline drugs for the treatment of uncomplicated malaria is now widespread in South East Asia (SEA). However, ACTs remain efficacious in sSA though in vivo delayed parasite clearance and in vitro reduced susceptibility to both components of the drug has been reported. Resistance to ACTs is therefore anticipated especially with its sustained use in endemic regions and the recent report of the emergence of de novo Pfk13 mutation that is now spreading in Rwanda. In The Gambia where artemether-lumefantrine (AL) is the first-line drug used for over 10 years, a steady increase in parasite tolerance to lumefantrine (LUM) was observed over a period of 4 years which strongly correlated with reported directional selection on a cysteine desulfarase gene (Pfnfs1). These findings are concerning and require continuous drug surveillance to track spontaneous development of AL resistant parasites and determine pathways to resistance development. This study therefore sought to investigate the prevalence and mechanisms of parasite tolerance to AL in The Gambia. A novel ex vivo drug susceptibility assay suitable to simultaneously assess parasite responses to both drugs used in AL was developed and used to assess drug susceptibility profiles of circulating parasites in western Gambia. This assay was then used to confirm identified potent compounds from the Medicines for Malaria Venture pathogen box effective against the erythrocytic stages of the parasite for future development into new antimalarial drugs. The prevalence of known drug resistance markers was assessed and novel markers that could be associated with drug resistance identified using both regression analysis and GWAS approach. Finally, CRISPR-Cas9 genome editing was used to functionally validate Pfnfs1 for its involvement in LUM tolerance using gene editing approaches. Keywords: Malaria, antimalarial drug resistance, ex vivo drug assays, high throughput screening genotyping, functional analysis, association studies