Dataset Information

Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin.

ABSTRACT: Novel antimalarial therapies are needed in the face of emerging resistance to artemisinin combination therapies. A previous study found a high cure rate in Mozambican children with uncomplicated Plasmodium falciparum malaria 7 days after combination treatment with fosmidomycin-clindamycin. However, 28-day cure rates were low (45.9%), owing to parasite recrudescence. We sought to identify any genetic changes underlying parasite recrudescence. To this end, we used a selective whole-genome amplification method to amplify parasite genomes from blood spot DNA samples. Parasite genomes from pretreatment and postrecrudescence samples were subjected to whole-genome sequencing to identify nucleotide variants. Our data did not support the existence of a genetic change responsible for recrudescence following fosmidomycin-clindamycin treatment. Additionally, we found that previously described resistance alleles for these drugs do not represent biomarkers of recrudescence. Future studies should continue to optimize fosmidomycin combinations for use as antimalarial therapies.

SUBMITTER: Guggisberg AM

PROVIDER: S-EPMC5021231 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin.

Guggisberg Ann M AM Sundararaman Sesh A SA Lanaspa Miguel M Moraleda Cinta C González Raquel R Mayor Alfredo A Cisteró Pau P Hutchinson David D Kremsner Peter G PG Hahn Beatrice H BH Bassat Quique Q Odom Audrey R AR

The Journal of infectious diseases 20160720 7

Novel antimalarial therapies are needed in the face of emerging resistance to artemisinin combination therapies. A previous study found a high cure rate in Mozambican children with uncomplicated Plasmodium falciparum malaria 7 days after combination treatment with fosmidomycin-clindamycin. However, 28-day cure rates were low (45.9%), owing to parasite recrudescence. We sought to identify any genetic changes underlying parasite recrudescence. To this end, we used a selective whole-genome amplific ...[more]

PMID: 27443612

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Project description:Antimicrobial drug resistance is an urgent problem in the control and treatment of many of the world's most serious infections, including Plasmodium falciparum malaria, tuberculosis, and healthcare-associated infections with Gram-negative bacteria. Because the non-mevalonate pathway of isoprenoid biosynthesis is essential in eubacteria and P. falciparum and this pathway is not present in humans, there is great interest in targeting the enzymes of non-mevalonate metabolism for antibacterial and antiparasitic drug development. Fosmidomycin is a broad-spectrum antimicrobial agent currently in clinical trials of combination therapies for the treatment of malaria. In vitro, fosmidomycin is known to inhibit the deoxyxylulose phosphate reductoisomerase (DXR) enzyme of isoprenoid biosynthesis from multiple pathogenic organisms. To define the in vivo metabolic response to fosmidomycin, we developed a novel mass spectrometry method to quantitate six metabolites of non-mevalonate isoprenoid metabolism from complex biological samples. Using this technique, we validate that the biological effects of fosmidomycin are mediated through blockade of de novo isoprenoid biosynthesis in both P. falciparum malaria parasites and Escherichia coli bacteria: in both organisms, metabolic profiling demonstrated a block of isoprenoid metabolism following fosmidomycin treatment, and growth inhibition due to fosmidomycin was rescued by media supplemented with isoprenoid metabolites. Isoprenoid metabolism proceeded through DXR even in the presence of fosmidomycin but was inhibited at the level of the downstream enzyme, methylerythritol phosphate cytidyltransferase (IspD). Overexpression of IspD in E. coli conferred fosmidomycin resistance, and fosmidomycin was found to inhibit IspD in vitro. This work has validated fosmidomycin as a biological reagent for blocking non-mevalonate isoprenoid metabolism and suggests a second in vivo target for fosmidomycin within isoprenoid biosynthesis, in two evolutionarily diverse pathogens.

Dataset Information

Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin.

Publications

Whole-Genome Sequencing to Evaluate the Resistance Landscape Following Antimalarial Treatment Failure With Fosmidomycin-Clindamycin.

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