Biology subjects

Sauerwein, R.

Publications and source records attributed to Sauerwein, R..

3 recordsLinked to original sources

bioRxiv2018

Antimalarial pantothenamide metabolites target acetyl-CoA synthesis in Plasmodium falciparum

Malaria eradication is critically dependent on novel drugs that target resistant Plasmodium parasites and block transmission of the disease. Here we report the discovery of potent pantothenamide bioisosteres that are active against blood-stage P. falciparum and also block onward mosquito transmission. These compounds are resistant to degradation by serum pantetheinases, show favorable pharmacokinetic properties and clear parasites in a humanized rodent infection model. Metabolomics revealed that CoA biosynthetic enzymes convert pantothenamides into drug-conjugates that interfere with parasite acetyl-CoA anabolism. In vitro generated resistant parasites showed mutations in acetyl-CoA synthetase and acyl-CoA synthetase 11, confirming the key roles of these enzymes in the sensitivity to pantothenamides. These new pantothenamides provide a promising class of antimalarial drugs with a unique mode of action.\n\nOne sentence summaryPantothenamides form antimetabolites that interfere with acetyl-CoA metabolism in the human malaria parasite Plasmodium falciparum

pharmacology and toxicology↗

bioRxiv2017

Probabilistic data integration identifies reliable gametocyte-specific proteins and transcripts in malaria parasites

Plasmodium gametocytes are the sexual forms of the malaria parasite essential for transmission to mosquitoes. To better understand how gametocytes differ from asexual blood-stage parasites, we performed a systematic analysis of available omics data for P. falciparum and other Plasmodium species. 18 transcriptomic and proteomic data sets were evaluated for the presence of curated \"gold standards\" of 41 gametocyte-specific versus 46 non-gametocyte genes and integrated using Bayesian probabilities, resulting in gametocyte-specificity scores for all P. falciparum genes.\n\nTo illustrate the utility of the gametocyte score, we explored newly predicted gametocyte-specific genes as potential biomarkers of gametocyte carriage and exposure. We analyzed the humoral immune response in field samples against 30 novel gametocyte-specific antigens and found five antigens to be differentially recognized by gametocyte carriers as compared to malaria-infected individuals without detectable gametocytes. We also validated the gametocyte-specificity of 15 identified gametocyte transcripts on culture material and samples from naturally infected individuals, resulting in eight transcripts that were >1000-fold higher expressed in gametocytes compared to asexual parasites and whose transcript abundance allowed gametocyte detection in naturally infected individuals. Our integrated genome-wide gametocyte-specificity scores provide a comprehensive resource to identify targets and monitor P. falciparum gametocytemia.

microbiology↗

bioRxiv2017

Mosquito lipids regulate Plasmodium sporogony and infectivity to the mammalian host

Malaria is a fatal human parasitic disease transmitted by a mosquito vector. The evolution of within-host malaria virulence has been the focus of many empirical and theoretical studies. However, the vectors contribution to virulence evolution is not well understood. Here we explored how within-vector resource exploitation impacts evolutionary trajectories of within-host Plasmodium virulence. We developed a nested model of within-vector dynamics and malaria epidemiology, which predicted that non-competitive resource exploitation within-vector restricts within-host parasite virulence. To validate our model, we experimentally manipulated mosquito lipid trafficking and gauged within-vector parasite development, within-host infectivity and virulence. We found that mosquito-derived lipids determine within-host parasite virulence by shaping development and metabolic activity of transmissible sporozoites. Our findings uncover the role of within-vector environment in regulating within-host Plasmodium virulence and identify Plasmodium metabolic traits that may contribute to the evolution of malaria virulence.

microbiology↗