The impact of antimalarial drug resistance mutations on parasite fitness, and its implications for the evolution of resistance

2005 ◽  
Vol 8 (1-2) ◽  
pp. 43-50 ◽  
Author(s):  
I HASTINGS ◽  
M DONNELLY
Keyword(s):  
Drug Resistance ◽  
Antimalarial Drug ◽  
Resistance Mutations ◽  
Antimalarial Drug Resistance ◽  
Parasite Fitness ◽  
Drug Resistance Mutations ◽  
Evolution Of Resistance ◽  
The Impact

scholarly journals Describing the current status of Plasmodium falciparum population structure and drug resistance within mainland Tanzania using molecular inversion probes

2020 ◽  
Author(s):  
Kara A. Moser ◽  
Rashid A. Madebe ◽  
Ozkan Aydemir ◽  
Mercy G. Chiduo ◽  
Celine I. Mandara ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Plasmodium Falciparum ◽  
Population Structure ◽  
Genetic Relatedness ◽  
Sub Saharan Africa ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Molecular Inversion Probes ◽  
Parasite Populations ◽  
The Impact

ABSTRACTHigh-throughput Plasmodium genomic data is increasingly useful in assessing prevalence of clinically important mutations and malaria transmission patterns. Understanding parasite diversity is important for identification of specific human or parasite populations that can be targeted by control programs, and to monitor the spread of mutations associated with drug resistance. An up-to-date understanding of regional parasite population dynamics is also critical to monitor the impact of control efforts. However, this data is largely absent from high-burden nations in Africa, and to date, no such analysis has been conducted for malaria parasites in Tanzania country-wide. To this end, over 1,000 P. falciparum clinical isolates were collected in 2017 from 13 sites in seven administrative regions across Tanzania, and parasites were genotyped at 1,800 variable positions genome-wide using molecular inversion probes. Population structure was detectable among Tanzanian P. falciparum parasites, roughly separating parasites from the northern and southern districts and identifying genetically admixed populations in the north. Isolates from geographically close districts were more likely to be genetically related compared to parasites sampled from more distant districts. Known drug resistance mutations were seen at increased frequency in northern districts, and additional variants with undetermined significance for antimalarial resistance also varied by geography. Malaria Indicator Survey (2017) data corresponded with genetic findings, including average region-level complexity-of-infection and malaria prevalence estimates. The parasite populations identified here provide important information on extant spatial patterns of genetic diversity of Tanzanian parasites, to which future surveys of genetic relatedness can be compared.SIGNIFICANCEDocumenting dynamics of malaria parasite genomics in high-transmission settings at scale in sub-Saharan Africa is critical for policy and decision making to support ongoing malaria elimination initiatives. Using molecular inversion probes, we genotyped over 1,000 Tanzanian Plasmodium falciparum samples collected country-wide in 2017 at hundreds of variable polymorphic positions across the genome. Frequencies of known drug resistance mutations were higher in northern districts of the country compared to the south. Results also showed a distinct isolation-by-distance pattern (whereby increasing geographic distance was correlated with decreasing genetic relatedness), as well as signals of higher genetic sharing between several southern districts. These results provide, for the first time, a picture of current within-country diversity of Tanzanian P. falciparum populations.

scholarly journals Dynamic changes in genetic diversity, drug resistance mutations, and treatment outcomes of falciparum malaria from the low-transmission to the pre-elimination phase on the isolated islands of São Tomé and Príncipe

2021 ◽  
Author(s):  
Ying-An Chen ◽  
Tsen-Ju Shiu ◽  
Lien-Fen Tseng ◽  
Chien-Fu Cheng ◽  
Wei-Liang Shih ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Drug Resistance ◽  
Treatment Outcomes ◽  
Resistance Mutations ◽  
Antimalarial Drug Resistance ◽  
Elimination Phase ◽  
Logistic Regression Models ◽  
Drug Resistance Mutations ◽  
Sao Tome And Principe

Abstract Background With effective vector control and case management, substantial progress has been made in the elimination of malaria on the islands of São Tomé and Príncipe (STP). During the critical period from the low-transmission to the pre-elimination phase, this study tracked the dynamic changes in the genetic diversity in Plasmodium falciparum, the distribution of antimalarial drug-resistance genes, and the treatment outcomes in patients to provide insights for the prevention of rebounded malaria in STP. Methods Dried blood spots (DBSs) and case follow-up data were collected from malaria patients who had visited the Central Hospital between 2010 and 2016. Genomic DNA of P. falciparum was extracted from DBSs. The polymorphic regions on the genes for merozoite surface proteins 1 and 2 (msp1 and msp2) were amplified in 118 pre-treatment samples to identify the genetic diversity of the infected parasites. Anti-malarial drug resistance mutations in the multi-drug resistance (pfmdr1), chloroquine resistance transporter (pfcrt), and kelch 13 (pfK13) genes were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing in 111 samples. Treatment outcomes were categorized based on the parasitological results from microscopy during the 28-day follow-up after treatment. Factors related to malaria recurrence were characterized by logistic regression models using case follow-up data (total number = 7,482). Results The circulating parasite strains in STP showed significant changes at the recent peak incidence in 2012, during which the prevalent allelic type in MSP1 changed from K1 to MAD20, and that in MSP2 changed from 3D7/IC to FC27. Genotyping results for antimalarial drug-resistance markers showed that the dominant alleles of pfmdr1 86 + 184 + 1246-pfcrt 76 were YFD-T (51.4%). Logistic regression models showed that significant factors related to parasitological failure after treatment were age (protective factor, OR = 0.97–0.98), log10-transformed parasite density (OR = 1.07–1.44), and treatment (quinine vs. artemisinin-based combination therapy, OR = 1.91–1.96). Overall, younger patients, those with higher parasitemia levels at enrollment, and those treated with quinine had a higher risk of recurrence during follow-up. Conclusions Although malaria treatment efficacy remained acceptable in STP, this study showed temporal changes in the dominant strains and the development of drug resistance mutations in the local parasite population. Therapeutic efficacy should be carefully monitored to adequately adjust the policy in the future.

scholarly journals The impact of HIV-1 on the malaria parasite biomass in adults in sub-Saharan Africa contributes to the emergence of antimalarial drug resistance

2008 ◽  
Vol 7 (1) ◽  
Author(s):  
Jean-Pierre Van geertruyden ◽  
Joris Menten ◽  
Robert Colebunders ◽  
Eline Korenromp ◽  
Umberto D'Alessandro
Keyword(s):  
Drug Resistance ◽  
Antimalarial Drug ◽  
Malaria Parasite ◽  
Sub Saharan Africa ◽  
Antimalarial Drug Resistance ◽  
Sub Saharan ◽  
The Impact ◽  
Hiv 1

scholarly journals Nutrient limitation magnifies fitness costs of antimalarial drug resistance mutations

2021 ◽  
Author(s):  
Shalini K Nair ◽  
Xue Li ◽  
Grace Ann Arya ◽  
Marina McDew-White ◽  
Marco Ferrari ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Resource Competition ◽  
Culture Media ◽  
Fold Increase ◽  
Single Amino Acid ◽  
Resistance Mutations ◽  
Fitness Costs ◽  
Drug Resistance Mutations ◽  
The Impact

Drug resistance mutations tend to disrupt key physiological processes, and therefore carry a fitness cost. The size of these fitness costs is a central determinant of the rate of spread of these mutations in natural populations so are important to quantify. Head-to-head competition assays provide a standard approach to measuring differential fitness, and have been used extensively for malaria parasites. These assays typically use standardized culture media, containing RPMI 1640, which has a 1.4 to 5.5-fold (mean: 2.6-fold) higher concentration of amino acids than human blood. In this rich media we predict that fitness costs will be underestimated because resource competition is weak. We tested this prediction using an artemisinin sensitive parasite edited to contain kelch-C580Y or R561H mutations conferring resistance to artemisinin or synonymous control mutations. We examined the impact of these single amino acid mutations on fitness, using replicated head-to head competition experiments conducted in media containing (i) normal RPMI, (ii) modified RPMI with reduced amino acid concentration, (iii) RPMI containing only isoleucine, or (iv) 3-fold diluted RPMI. We found a significant 1.3 to 1.4-fold increase in fitness costs measured in modified and isoleucine-only media relative to normal media, while fitness costs were 2.5-fold higher in diluted media. We conclude that fitness costs are strongly affected by media composition and will be significantly underestimated in normal RPMI. Elevated fitness costs in nature will limit spread of ART-resistance but will also promote evolution of compensatory mutations that restore fitness, and can be exploited to maximize selection in laboratory experiments.

scholarly journals Influence of Drug Resistance Mutations on the Activity of HIV-1 Subtypes A and B Integrases: a Comparative Study

Acta Naturae ◽  
2015 ◽  
Vol 7 (1) ◽  
pp. 78-86 ◽  
Author(s):  
O. A. Shadrina ◽  
T. S. Zatsepin ◽  
Yu. Yu. Agapkina ◽  
M. G. Isaguliants ◽  
M. B. Gottikh
Keyword(s):  
Drug Resistance ◽  
Comparative Study ◽  
Gene Mutations ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Primary Resistance ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
The Impact ◽  
Hiv 1

Integration of human immunodeficiency virus (HIV-1) DNA into the genome of an infected cell is one of the key steps in the viral replication cycle. The viral enzyme integrase (IN), which catalyzes the integration, is an attractive target for the development of new antiviral drugs. However, the HIV-1 therapy often results in the IN gene mutations inducing viral resistance to integration inhibitors. To assess the impact of drug resistance mutations on the activity of IN of HIV-1 subtype A strain FSU-A, which is dominant in Russia, variants of the consensus IN of this subtype containing the primary resistance mutations G118R and Q148K and secondary compensatory substitutions E138K and G140S were prepared and characterized. Comparative study of these enzymes with the corresponding mutants of IN of HIV-1 subtype B strains HXB-2 was performed. The mutation Q148K almost equally reduced the activity of integrases of both subtypes. Its negative effect was partially compensated by the secondary mutations E138K and G140S. Primary substitution G118R had different influence on the activity of proteins of the subtypes A and B, and the compensatory effect of the secondary substitution E138K also depended on the viral subtype. Comparison of the mutants resistance to the known strand transfer inhibitors raltegravir and elvitegravir, and a new inhibitor XZ-259 (a dihydro-1H-isoindol derivative), showed that integrases of both subtypes with the Q148K mutation were insensitive to raltegravir and elvitegravir but were effectively inhibited by XZ-259. The substitution G118R slightly reduced the efficiency of IN inhibition by raltegravir and elvitegravir and caused no resistance to XZ_259.

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