Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites
Frontline drug treatments for malaria are at risk of failing due to emerging resistance, meanwhile drugs used to treat toxoplasmosis have suboptimal efficacy and safety. As demonstrated by the success of clinically used antiparasitic drugs, the diverse structural complexity and biological activity o...
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| Format: | Article |
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Elsevier
2025-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320725000296 |
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| author | Maria R. Gancheva Emma Y. Mao Ornella Romeo Daniel Vuong Ryan O'Handley Stephen W. Page Ernest Lacey Danny W. Wilson |
| author_facet | Maria R. Gancheva Emma Y. Mao Ornella Romeo Daniel Vuong Ryan O'Handley Stephen W. Page Ernest Lacey Danny W. Wilson |
| author_sort | Maria R. Gancheva |
| collection | DOAJ |
| description | Frontline drug treatments for malaria are at risk of failing due to emerging resistance, meanwhile drugs used to treat toxoplasmosis have suboptimal efficacy and safety. As demonstrated by the success of clinically used antiparasitic drugs, the diverse structural complexity and biological activity of natural products holds great potential for drug discovery and development, to address the need for new compounds with novel mechanisms. Here we screened the BioAustralis Discovery Plates Series I library, a collection of 812 microbial natural product compounds including rare microbial metabolites, against Plasmodium falciparum erythrocytic stage and Toxoplasma gondii tachyzoite parasites. We identified 219 compounds that inhibited P. falciparum growth by at least 80 % at a concentration of 2 μg/mL (1–10 μM for >90 % of compounds), whilst 149 compounds demonstrated equivalent activity against T. gondii. The active compounds were assigned based on chemical structure to more than 50 compound classes. After triaging active compounds for those with low mammalian cytotoxicity, we defined the in vitro half maximal inhibitory concentration (IC50) of a selection of compounds against the parasites, identifying four compound groups with activity in the low nanomolar range. The macrocyclic lactone pladienolide B and cryptopleurine were found to be very potent against the parasites but also mammalian cells, warranting further structure-activity relationship investigation. Two groups, the monocyclic thiazole peptides, including micrococcin P1 and the thiocillins, and the pleuromutilins, exhibited both low antiparasitic IC50 and low cytotoxicity, highlighting their potential for further analysis. This study defines the activity of the BioAustralis Discovery Plates Series I against two apicomplexan parasites of significant global importance, providing potential new tools to study parasite biology and possible starting points for novel antiparasitic development. |
| format | Article |
| id | doaj-art-af439f17d35445e2aa640e01dcfef959 |
| institution | Kabale University |
| issn | 2211-3207 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj-art-af439f17d35445e2aa640e01dcfef9592025-08-22T04:56:12ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072025-12-012910060610.1016/j.ijpddr.2025.100606Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasitesMaria R. Gancheva0Emma Y. Mao1Ornella Romeo2Daniel Vuong3Ryan O'Handley4Stephen W. Page5Ernest Lacey6Danny W. Wilson7Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, South Australia, Australia; ARC Training Centre for Environmental and Agricultural Solutions to Antimicrobial Resistance (CEAStAR), St Lucia, 4072, Queensland, Australia; School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, 5371, South Australia, Australia; Corresponding author. Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, South Australia, Australia.Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, South Australia, Australia; ARC Training Centre for Environmental and Agricultural Solutions to Antimicrobial Resistance (CEAStAR), St Lucia, 4072, Queensland, AustraliaResearch Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, South Australia, AustraliaMicrobial Screening Technologies Pty Ltd, Smithfield, 2164, New South Wales, AustraliaSchool of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, 5371, South Australia, AustraliaNeoculi Pty Ltd, Newtown, 2042, New South Wales, AustraliaMicrobial Screening Technologies Pty Ltd, Smithfield, 2164, New South Wales, AustraliaResearch Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, South Australia, Australia; ARC Training Centre for Environmental and Agricultural Solutions to Antimicrobial Resistance (CEAStAR), St Lucia, 4072, Queensland, Australia; Burnet Institute, Melbourne, 3004, Victoria, Australia; Corresponding author. Research Centre for Infectious Diseases, School of Biological Sciences, The University of Adelaide, Adelaide, 5005, South Australia, Australia.Frontline drug treatments for malaria are at risk of failing due to emerging resistance, meanwhile drugs used to treat toxoplasmosis have suboptimal efficacy and safety. As demonstrated by the success of clinically used antiparasitic drugs, the diverse structural complexity and biological activity of natural products holds great potential for drug discovery and development, to address the need for new compounds with novel mechanisms. Here we screened the BioAustralis Discovery Plates Series I library, a collection of 812 microbial natural product compounds including rare microbial metabolites, against Plasmodium falciparum erythrocytic stage and Toxoplasma gondii tachyzoite parasites. We identified 219 compounds that inhibited P. falciparum growth by at least 80 % at a concentration of 2 μg/mL (1–10 μM for >90 % of compounds), whilst 149 compounds demonstrated equivalent activity against T. gondii. The active compounds were assigned based on chemical structure to more than 50 compound classes. After triaging active compounds for those with low mammalian cytotoxicity, we defined the in vitro half maximal inhibitory concentration (IC50) of a selection of compounds against the parasites, identifying four compound groups with activity in the low nanomolar range. The macrocyclic lactone pladienolide B and cryptopleurine were found to be very potent against the parasites but also mammalian cells, warranting further structure-activity relationship investigation. Two groups, the monocyclic thiazole peptides, including micrococcin P1 and the thiocillins, and the pleuromutilins, exhibited both low antiparasitic IC50 and low cytotoxicity, highlighting their potential for further analysis. This study defines the activity of the BioAustralis Discovery Plates Series I against two apicomplexan parasites of significant global importance, providing potential new tools to study parasite biology and possible starting points for novel antiparasitic development.http://www.sciencedirect.com/science/article/pii/S2211320725000296Drug discoveryNatural productsMalariaToxoplasmosis |
| spellingShingle | Maria R. Gancheva Emma Y. Mao Ornella Romeo Daniel Vuong Ryan O'Handley Stephen W. Page Ernest Lacey Danny W. Wilson Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites International Journal for Parasitology: Drugs and Drug Resistance Drug discovery Natural products Malaria Toxoplasmosis |
| title | Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites |
| title_full | Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites |
| title_fullStr | Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites |
| title_full_unstemmed | Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites |
| title_short | Screening and hit evaluation of a microbial metabolite library against the pathogenic Plasmodium falciparum and Toxoplasma gondii parasites |
| title_sort | screening and hit evaluation of a microbial metabolite library against the pathogenic plasmodium falciparum and toxoplasma gondii parasites |
| topic | Drug discovery Natural products Malaria Toxoplasmosis |
| url | http://www.sciencedirect.com/science/article/pii/S2211320725000296 |
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