scholarly journals The interplay between drug resistance and fitness in malaria parasites

2013 ◽  
Vol 89 (6) ◽  
pp. 1025-1038 ◽  
Author(s):  
Philip J. Rosenthal
Keyword(s):  
Drug Resistance ◽  
Malaria Parasites

scholarly journals Assessment of the Drug Susceptibility of Plasmodium falciparum Clinical Isolates from Africa by Using a Plasmodium Lactate Dehydrogenase Immunodetection Assay and an Inhibitory Maximum Effect Model for Precise Measurement of the 50-Percent Inhibitory Concentration

2006 ◽  
Vol 50 (10) ◽  
pp. 3343-3349 ◽  
Author(s):  
Halima Kaddouri ◽  
Serge Nakache ◽  
Sandrine Houzé ◽  
France Mentré ◽  
Jacques Le Bras
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Lactate Dehydrogenase ◽  
Active Metabolite ◽  
Inhibitory Concentration ◽  
Drug Susceptibility ◽  
Maximum Effect ◽  
Malaria Parasites ◽  
Effect Model

ABSTRACT The extension of drug resistance among malaria-causing Plasmodium falciparum parasites in Africa necessitates implementation of new combined therapeutic strategies. Drug susceptibility phenotyping requires precise measurements. Until recently, schizont maturation and isotopic in vitro assays were the only methods available, but their use was limited by technical constraints. This explains the revived interest in the development of replacement methods, such as the Plasmodium lactate dehydrogenase (pLDH) immunodetection assay. We evaluated a commercially controlled pLDH enzyme-linked immunosorbent assay (ELISA; the ELISA-Malaria antigen test; DiaMed AG, Cressier s/Morat, Switzerland) to assess drug susceptibility in a standard in vitro assay using fairly basic laboratory equipment to study the in vitro resistance of malaria parasites to major antimalarials. Five Plasmodium falciparum clones and 121 clinical African isolates collected during 2003 and 2004 were studied by the pLDH ELISA and the [8-3H]hypoxanthine isotopic assay as a reference with four antimalarials. Nonlinear regression with a maximum effect model was used to estimate the 50% inhibitory concentration (IC50) and its confidence intervals. The two methods were observed to have similar reproducibilities, but the pLDH ELISA demonstrated a higher sensitivity. The high correlation (r = 0.98) and the high phenotypic agreement (κ = 0.88) between the two methods allowed comparison by determination of the IC50s. Recently collected Plasmodium falciparum African isolates were tested by pLDH ELISA and showed drug resistance or decreased susceptibilities of 62% to chloroquine and 11.5% to the active metabolite of amodiaquine. No decreased susceptibility to lumefantrine or the active metabolite of artemisinin was detected. The availability of this simple and highly sensitive pLDH immunodetection assay will provide an easier method for drug susceptibility testing of malaria parasites.

scholarly journals Pooled Sequencing and Rare Variant Association Tests for Identifying the Determinants of Emerging Drug Resistance in Malaria Parasites

2015 ◽  
Vol 32 (4) ◽  
pp. 1080-1090 ◽  
Author(s):  
Ian H. Cheeseman ◽  
Marina McDew-White ◽  
Aung Pyae Phyo ◽  
Kanlaya Sriprawat ◽  
François Nosten ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Rare Variant ◽  
Malaria Parasites ◽  
Rare Variant Association ◽  
Association Tests ◽  
Pooled Sequencing

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 Nanopore sequencing of drug-resistance-associated genes in malaria parasites, Plasmodium falciparum

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Lucky R. Runtuwene ◽  
Josef S. B. Tuda ◽  
Arthur E. Mongan ◽  
Wojciech Makalowski ◽  
Martin C. Frith ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Nanopore Sequencing ◽  
Malaria Parasites

scholarly journals Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Vasantha Rao Dola ◽  
Awakash Soni ◽  
Pooja Agarwal ◽  
Hafsa Ahmad ◽  
Kanumuri Siva Rama Raju ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Solid State ◽  
Side Chain ◽  
Detailed Structure ◽  
Preclinical Development ◽  
Malaria Parasites ◽  
Sar Studies ◽  
Structure Activity

ABSTRACT A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.

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 Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4858 ◽  
Author(s):  
Despina Palla ◽  
Antonia I. Antoniou ◽  
Michel Baltas ◽  
Christophe Menendez ◽  
Philippe Grellier ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Infectious Diseases ◽  
Antimalarial Activity ◽  
Biological Evaluation ◽  
Antiplasmodial Activity ◽  
Malaria Parasites ◽  
Antimalarial Agents ◽  
New Compounds

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5–5.4 and 41.5–23.1 times more potent activities than FSM, respectively.

scholarly journals Plasmodium Species and Drug Resistance

2021 ◽  
Author(s):  
Sintayehu Tsegaye Tseha
Keyword(s):  
Drug Resistance ◽  
Artemisinin Resistance ◽  
Plasmodium Species ◽  
Public Health Problem ◽  
Antimalarial Drugs ◽  
Chloroquine Resistance ◽  
Resistance Pattern ◽  
Malaria Parasites ◽  
Human Malaria ◽  
The World

Malaria is a leading public health problem in tropical and subtropical countries of the world. In 2019, there were an estimated 229 million malaria cases and 409, 000 deaths due malaria in the world. The objective of this chapter is to discuss about the different Plasmodium parasites that cause human malaria. In addition, the chapter discusses about antimalarial drugs resistance. Human malaria is caused by five Plasmodium species, namely P. falciparum, P. malariae, P. vivax, P. ovale and P. knowlesi. In addition to these parasites, malaria in humans may also arise from zoonotic malaria parasites, which includes P. inui and P. cynomolgi. The plasmodium life cycle involves vertebrate host and a mosquito vector. The malaria parasites differ in their epidemiology, virulence and drug resistance pattern. P. falciparum is the deadliest malaria parasite that causes human malaria. P. falciparum accounted for nearly all malarial deaths in 2018. One of the major challenges to control malaria is the emergence and spread of antimalarial drug-resistant Plasmodium parasites. The P. vivax and P. falciparum have already developed resistance against convectional antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, and atovaquone. Chloroquine-resistance is connected with mutations in pfcr. Resistance to Sulfadoxine and pyrimethamine is associated with multiple mutations in pfdhps and pfdhfr genes. In response to the evolution of drug resistance Plasmodium parasites, artemisinin-based combination therapies (ACTs) have been used for the treatment of uncomplicated falciparum malaria since the beginning of 21th century. However, artemisinin resistant P. falciparum strains have been recently observed in different parts of the world, which indicates the possibility of the spread of artemisinin resistance to all over the world. Therefore, novel antimalarial drugs have to be searched so as to replace the ACTs if Plasmodium parasites develop resistance to ACTs in the future.

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