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Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes

CiteULike malaria tags - 5 April 2017 - 9:41am
International Journal for Parasitology: Drugs and Drug Resistance, Vol. 7, No. 2. (August 2017), pp. 174-180, doi:10.1016/j.ijpddr.2017.03.001

Genetic diversity of 11gene-targets of new antimalarial compounds was investigated. Genetic data was analysed for 18 malaria endemic countries. No signals of selective pressure was observed. A mutation linked to resistance to a new antimalarial was found in African parasites. Amino-acid changes close to reported antimalarial resistant mutations were detected. Drug resistance is a recurrent problem in the fight against malaria. Genetic and epidemiological surveillance of antimalarial resistant parasite alleles is crucial to guide drug therapies and clinical management. New antimalarial compounds are currently at various stages of clinical trials and regulatory evaluation. Using ∼2000 Plasmodium falciparum genome sequences, we investigated the genetic diversity of eleven gene-targets of promising antimalarial compounds and assessed their potential efficiency across malaria endemic regions. We determined if the loci are under selection prior to the introduction of new drugs and established a baseline of genetic variance, including potential resistant alleles, for future surveillance programmes.
Ana Gomes, Matt Ravenhall, Ernest Benavente, Arthur Talman, Colin Sutherland, Cally Roper, Taane Clark, Susana Campino
Categories: malaria news feeds

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

CiteULike malaria tags - 23 March 2017 - 1:37pm
Nature communications, Vol. 8 (06 March 2017)

Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 and 0.57 mg kg(-1), respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.
Ebere Sonoiki, Caroline Ng, Marcus Lee, Denghui Guo, Yong-Kang Zhang, Yasheen Zhou, MR Alley, Vida Ahyong, Laura Sanz, Maria Jose Lafuente-Monasterio, Chen Dong, Patrick Schupp, Jiri Gut, Jenny Legac, Roland Cooper, Francisco-Javier Gamo, Joseph DeRisi, Yvonne Freund, David Fidock, Philip Rosenthal
Categories: malaria news feeds

A Surface Phospholipase Is Involved in the Migration of Plasmodium Sporozoites through Cells

CiteULike malaria tags - 20 March 2017 - 10:28pm
Journal of Biological Chemistry, Vol. 280, No. 8. (25 February 2005), pp. 6752-6760, doi:10.1074/jbc.m411465200

Plasmodium sporozoites, injected by mosquitoes into the skin of the host, traverse cells during their migration to hepatocytes where they continue their life cycle. The mechanisms used by the parasite to rupture the plasma membrane of the host cells are not known. Here we report the presence of a phospholipase on the surface of Plasmodium berghei sporozoites (P. berghei phospholipase; Pb PL) and demonstrate that it is involved in the establishment of a malaria infection in vivo. Pb PL is highly conserved among the Plasmodium species. The protein is about 750 amino acids, with a predicted signal sequence and a carboxyl terminus that is 32% identical to the vertebrate lecithin:cholesterol acyltransferase, a secreted phospholipase. Pb PL contains a motif characteristic of lipases and a catalytic triad of a serine, aspartate, and histidine that is found in several phospholipases. We have verified its lipase and membrane lytic activity in vitro, using recombinant baculovirus-expressed protein. To study its role in vivo, we have disrupted the P. berghei PL open reading frame and generated mutants in its active site. During an infection through mosquito bite, the infectivity of the knock-out parasites in the liver is decreased by ∼90%. The prepatent period of the resulting blood infection is 1 day longer as compared with wild type. Further, the mutant sporozoites are impaired in their ability to cross epithelial cell layers. Thus, the Pb PL functions as a lipase to damage cell membranes and facilitates sporozoite passage through cells during their migration from the skin to the bloodstream.
Purnima Bhanot, Kristine Schauer, Isabelle Coppens, Victor Nussenzweig
Categories: malaria news feeds

Genetic diversity of next generation antimalarial targets: A baseline for drug resistance surveillance programmes

CiteULike malaria tags - 20 March 2017 - 12:35pm
International Journal for Parasitology: Drugs and Drug Resistance (March 2017), doi:10.1016/j.ijpddr.2017.03.001

Genetic diversity of 11gene-targets of new antimalarial compounds was investigated. Genetic data was analyzed for 18 malaria endemic countries. No signals of selective pressure was observed. A mutation linked to resistance to a new antimalarial was found in African parasites. Amino-acid changes close to reported antimalarial resistant mutations were detected. Drug resistance is a recurrent problem in the fight against malaria. Genetic and epidemiological surveillance of antimalarial resistant parasite alleles is crucial to guide drug therapies and clinical management. New antimalarial compounds are currently at various stages of clinical trials and regulatory evaluation. Using ∼2000 Plasmodium falciparum genome sequences, we investigated the genetic diversity of eleven gene-targets of promising antimalarial compounds and assessed their potential efficiency across malaria endemic regions. We determined if the loci are under selection prior to the introduction of new drugs and established a baseline of genetic variance, including potential resistant alleles, for future surveillance programmes.
Ana Gomes, Matt Ravenhall, Ernest Benavente, Arthur Talman, Colin Sutherland, Cally Roper, Taane Clark, Susana Campino
Categories: malaria news feeds

Migration through host cells activates Plasmodium sporozoites for infection

CiteULike malaria tags - 17 March 2017 - 1:41pm
Nature Medicine, Vol. 8, No. 11. (15 October 2002), pp. 1318-1322, doi:10.1038/nm785

Plasmodium sporozoites, the infective stage of the malaria parasite transmitted by mosquitoes, migrate through several hepatocytes before infecting a final one. Migration through hepatocytes occurs by breaching their plasma membranes, and final infection takes place with the formation of a vacuole around the sporozoite1. Once in the liver, sporozoites have already reached their target cells, making migration through hepatocytes prior to infection seem unnecessary. Here we show that this migration is required for infection of hepatocytes. Migration through host cells, but not passive contact with hepatocytes, induces the exocytosis of sporozoite apical organelles, a prerequisite for infection with formation of a vacuole. Sporozoite activation induced by migration through host cells is an essential step of Plasmodium life cycle.
Maria Mota, Julius Hafalla, Ana Rodriguez
Categories: malaria news feeds

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