Research Articles Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum

Malaria eradication is critically dependent on new therapeutics that target resistant Plasmodium parasites and block transmission of the disease. Here, we report that pantothenamide bioisosteres were active against blood-stage Plasmodium falciparum parasites and also blocked transmission of sexual stages to the mosquito vector. These compounds were resistant to degradation by serum pantetheinases, showed favorable pharmacokinetic properties, and cleared parasites in a humanized mouse model of P. falciparum infection. Metabolomics revealed that coenzyme A biosynthetic enzymes converted pantothenamides into coenzyme A analogs that interfered with parasite acetyl–coenzyme A anabolism. Resistant parasites generated in vitro showed mutations in acetyl–coenzyme A synthetase and acyl–coenzyme A synthetase 11. Introduction and reversion of these mutations in P. falciparum using CRISPR-Cas9 gene editing confirmed the roles of these enzymes in the sensitivity of the malaria parasites to pantothenamides. These pantothenamide compounds with a new mode of action may have potential as drugs against malaria parasites.
Source: Science Translational Medicine - Category: Biomedical Science Authors: Tags: Research Articles Source Type: research

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Scientists who resurrected a 50,000-year-old gene sequence have analyzed it to figure out how the world's deadliest malaria parasite jumped from gorillas to humans - giving insight into the origins of one of human history's biggest killers.
Source: Reuters: Health - Category: Consumer Health News Tags: healthNews Source Type: news
Date: Wednesday, 11 13, 2019; Speaker: Laura Amo, Ph.D. , Postdoctoral Fellow, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases; Building: Building 45 (Natcher Building); Ruth Kirschstein Auditorium
Source: NIH Calendar of Events - Category: American Health Source Type: events
We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.
Source: Revista da Sociedade Brasileira de Medicina Tropical - Category: Tropical Medicine Source Type: research
Malaria is still a significant public health burden in the tropics. Infection with malaria causing parasites results in a wide range of clinical disease presentations, from severe to uncomplicated or mild, and in the poorly understood asymptomatic infections. The complexity of asymptomatic infections is due to the intricate interplay between factors derived from the human host, parasite, and environment. Asymptomatic infections often go undetected and provide a silent natural reservoir that sustains malaria transmission. This creates a major obstacle for malaria control and elimination efforts. Numerous studies have tried ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Malaria parasites undergo several stages in their complex lifecycle. To achieve reductions in both the individual disease burden and malaria transmission within communities, a multi-stage malaria vaccine with high effectiveness and durability is a more efficacious strategy compared with a single-stage vaccine. Here, we generated viral-vectored vaccines based on human adenovirus type 5 (AdHu5) and adeno-associated virus serotype 1 (AAV1) expressing a fusion protein of the pre-erythrocytic stage Plasmodium falciparum circumsporozoite protein (PfCSP) and the transmission-blocking sexual stage P25 protein (Pfs25). A two-dose h...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Journal of Medicinal ChemistryDOI: 10.1021/acs.jmedchem.9b01099
Source: Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research
by Xue Li, Sudhir Kumar, Marina McDew-White, Meseret Haile, Ian H. Cheeseman, Scott Emrich, Katie Button-Simons, Fran çois Nosten, Stefan H. I. Kappe, Michael T. Ferdig, Tim J. C. Anderson, Ashley M. Vaughan Determining the genetic basis of fitness is central to understanding evolution and transmission of microbial pathogens. In human malaria parasites (Plasmodium falciparum), most experimental work on fitness has focused on asexual blood stage parasites, because this stage can be easily cultured, although the transmission of malaria requires both femaleAnopheles mosquitoes and vertebrate hosts. We explore a powerf...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research
We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.
Source: Revista da Sociedade Brasileira de Medicina Tropical - Category: Tropical Medicine Source Type: research
We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.
Source: Revista da Sociedade Brasileira de Medicina Tropical - Category: Tropical Medicine Source Type: research
We reported three cases of possible parasite resistance to artemether-lumefantrine therapy. All subjects had complete parasite clearance when treated with other antimalarial drugs. This observation necessitates the urgent need to re-evaluate artemether-lumefantrine medication in Nigeria since it is one of the most commonly used ACT drug.
Source: Revista da Sociedade Brasileira de Medicina Tropical - Category: Tropical Medicine Source Type: research
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