scholarly journals Changes in Malaria Parasite Drug Resistance in an Endemic Population Over a 25-Year Period With Resulting Genomic Evidence of Selection

2013 ◽  
Vol 209 (7) ◽  
pp. 1126-1135 ◽  
Author(s):  
Davis C. Nwakanma ◽  
Craig W. Duffy ◽  
Alfred Amambua-Ngwa ◽  
Eniyou C. Oriero ◽  
Kalifa A. Bojang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Malaria Parasite ◽  
Endemic Population ◽  
Parasite Drug Resistance

scholarly journals Adaptive Drug Resistance in Malaria Parasite: A Threat to Malaria Elimination Agenda?

2021 ◽  
Author(s):  
Moses Okpeku
Keyword(s):  
Drug Resistance ◽  
Malaria Elimination ◽  
Malaria Parasite ◽  
Disease Burden ◽  
Drug Application ◽  
African Region ◽  
Malaria Parasites ◽  
Sub Saharan ◽  
Host Development

Malaria is a global disease of importance, especially in the sub-Saharan African region, where malaria accounts for great losses economically and to life. Fight to eliminate this disease has resulted in reduced disease burden in many places where the diseases is endemic. Elimination strategies in most places is focus on the use of treated nets and drug application. Exposure of malaria parasites to anti-malaria drugs have led to the evolution of drug resistance in both parasites and host. Development of drug resistance vary but, studies on adaptive drug resistance has implications and consequences. Our knowledge of this consequences are limited but important for the pursuit of an uninterrupted malaria elimination agenda. This chapter draws our attention to this risks and recommends interventions.

scholarly journals Sequence-based association and selection scans identify drug resistance loci in the Plasmodium falciparum malaria parasite

2012 ◽  
Vol 109 (32) ◽  
pp. 13052-13057 ◽  
Author(s):  
D. J. Park ◽  
A. K. Lukens ◽  
D. E. Neafsey ◽  
S. F. Schaffner ◽  
H.-H. Chang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Malaria Parasite ◽  
Plasmodium Falciparum Malaria

scholarly journals Mapping the malaria parasite drug-able genome using in vitro evolution and chemogenomics

2017 ◽  
Author(s):  
Annie N. Cowell ◽  
Eva S. Istvan ◽  
Amanda K. Lukens ◽  
Maria G. Gomez-Lorenzo ◽  
Manu Vanaerschot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Multidrug Resistance ◽  
Resistance Genes ◽  
Genome Analysis ◽  
Drug Targets ◽  
Malaria Parasite ◽  
Resistance Mechanisms ◽  
Whole Genome

AbstractChemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.One Sentence SummaryWhole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.

scholarly journals Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Ann M. Guggisberg ◽  
Philip M. Frasse ◽  
Andrew J. Jezewski ◽  
Natasha M. Kafai ◽  
Aakash Y. Gandhi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Malaria Parasite ◽  
Glycolytic Enzyme ◽  
Genetic Mechanism ◽  
Growth Defect ◽  
Malaria Parasites ◽  
Content Type ◽  
Metabolic Plasticity ◽  
Glycolytic Intermediates ◽  
Metabolic Regulators

ABSTRACT In the malaria parasite Plasmodium falciparum, synthesis of isoprenoids from glycolytic intermediates is essential for survival. The antimalarial fosmidomycin (FSM) inhibits isoprenoid synthesis. In P. falciparum, we identified a loss-of-function mutation in HAD2 (P. falciparum 3D7_1226300 [PF3D7_1226300]) as necessary for FSM resistance. Enzymatic characterization revealed that HAD2, a member of the haloacid dehalogenase-like hydrolase (HAD) superfamily, is a phosphatase. Harnessing a growth defect in resistant parasites, we selected for suppression of HAD2-mediated FSM resistance and uncovered hypomorphic suppressor mutations in the locus encoding the glycolytic enzyme phosphofructokinase 9 (PFK9). Metabolic profiling demonstrated that FSM resistance is achieved via increased steady-state levels of methylerythritol phosphate (MEP) pathway and glycolytic intermediates and confirmed reduced PFK9 function in the suppressed strains. We identified HAD2 as a novel regulator of malaria parasite metabolism and drug sensitivity and uncovered PFK9 as a novel site of genetic metabolic plasticity in the parasite. Our report informs the biological functions of an evolutionarily conserved family of metabolic regulators and reveals a previously undescribed strategy by which malaria parasites adapt to cellular metabolic dysregulation. IMPORTANCE Unique and essential aspects of parasite metabolism are excellent targets for development of new antimalarials. An improved understanding of parasite metabolism and drug resistance mechanisms is urgently needed. The antibiotic fosmidomycin targets the synthesis of essential isoprenoid compounds from glucose and is a candidate for antimalarial development. Our report identifies a novel mechanism of drug resistance and further describes a family of metabolic regulators in the parasite. Using a novel forward genetic approach, we also uncovered mutations that suppress drug resistance in the glycolytic enzyme PFK9. Thus, we identify an unexpected genetic mechanism of adaptation to metabolic insult that influences parasite fitness and tolerance of antimalarials.

scholarly journals Synergistic malaria vaccine combinations identified by systematic antigen screening

2017 ◽  
Vol 114 (45) ◽  
pp. 12045-12050 ◽  
Author(s):  
Leyla Y. Bustamante ◽  
Gareth T. Powell ◽  
Yen-Chun Lin ◽  
Michael D. Macklin ◽  
Nadia Cross ◽  
...  
Keyword(s):  
Malaria Elimination ◽  
Malaria Parasite ◽  
Malaria Vaccine ◽  
Specific Antigen ◽  
Mechanistic Explanation ◽  
Effective Vaccine ◽  
Clinical Testing ◽  
Erythrocyte Invasion ◽  
Endemic Population

A highly effective vaccine would be a valuable weapon in the drive toward malaria elimination. No such vaccine currently exists, and only a handful of the hundreds of potential candidates in the parasite genome have been evaluated. In this study, we systematically evaluated 29 antigens likely to be involved in erythrocyte invasion, an essential developmental stage during which the malaria parasite is vulnerable to antibody-mediated inhibition. Testing antigens alone and in combination identified several strain-transcending targets that had synergistic combinatorial effects in vitro, while studies in an endemic population revealed that combinations of the same antigens were associated with protection from febrile malaria. Video microscopy established that the most effective combinations targeted multiple discrete stages of invasion, suggesting a mechanistic explanation for synergy. Overall, this study both identifies specific antigen combinations for high-priority clinical testing and establishes a generalizable approach that is more likely to produce effective vaccines.

scholarly journals Predicting functional and regulatory divergence of a drug resistance transporter gene in the human malaria parasite

BMC Genomics ◽  
2015 ◽  
Vol 16 (1) ◽  
pp. 115 ◽  
Author(s):  
Geoffrey H Siwo ◽  
Asako Tan ◽  
Katrina A Button-Simons ◽  
Upeka Samarakoon ◽  
Lisa A Checkley ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Malaria Parasite ◽  
Transporter Gene ◽  
Human Malaria Parasite ◽  
Human Malaria
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