Origin of Robustness in Generating Drug-Resistant Malaria Parasites

Kümpornsin, Krittikorn; Modchang, Charin; Heinberg, Adina; Ekland, Eric H.; Jirawatcharadech, Piyaporn; Chobson, Pornpimol; Suwanakitti, Nattida; Chaotheing, Sastra; Wilairat, Prapon; Deitsch, Kirk W.; Kamchonwongpaisan, Sumalee; Fidock, David A.; Kirkman, Laura A.; Yuthavong, Yongyuth; Chookajorn, Thanat

doi:10.1093/molbev/msu140

Cited by 43 publications

(61 citation statements)

References 49 publications

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“…[13,51]); evidence for disproportionate competitive suppression of resistant parasites was observed only in Tanzania. One possible explanation is that the fitness difference between CQS and CQR strains is larger in Tanzania due to the genetic background(s) of one or both genotypes (epistatic effects on the fitness cost of resistance) [52,53].…”

Section: Discussionmentioning

confidence: 99%

Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum

et al. 2016

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Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed-strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high-transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures.

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Section: Discussionmentioning

confidence: 99%

Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum

et al. 2016

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“…Epistasis is also involved in fitness compensation in drug-resistant P. falciparum 56 . Mutations in dihydrofolate reductase (pfdhfr), which confer resistance to pyrimethamine, reduce parasite fitness and can be compensated for by the amplification of the first gene in the folate synthesis pathway, GTP cyclohydrolase 1 (pfgch1).…”

Section: Mechanisms Of Fitness Cost Compensationmentioning

confidence: 99%

“…Mutations in dihydrofolate reductase (pfdhfr), which confer resistance to pyrimethamine, reduce parasite fitness and can be compensated for by the amplification of the first gene in the folate synthesis pathway, GTP cyclohydrolase 1 (pfgch1). Because the amplification of pfgch1 itself confers low-level resistance, this amplification is probably selected early by the drug and reduces the cost of acquiring subsequent mutations in pfdhfr that further increase resistance 56 .…”

Section: Mechanisms Of Fitness Cost Compensationmentioning

confidence: 99%

“…a | Compensation by an intragenic mutation (dark green circle) is shown 46,47,53 . b | Compensation by increased dosage of a low-fitness mutant protein is shown 13,56 . c | Compensation by an intergenic mutation (dark green circle) is shown, which is relevant when protein complexes or protein interactions are involved in physiological activity 48,51 .…”

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confidence: 99%

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Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms

2015

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Drug therapy has a crucial role in the treatment of viral, bacterial, fungal and protozoan infections, as well as the control of human cancer. The success of therapy is being threatened by the increasing prevalence of resistance. We examine and compare mechanisms of drug resistance in these diverse biological systems (using HIV and Plasmodium falciparum as examples of viral and protozoan pathogens, respectively) and discuss how factors — such as mutation rates, fitness effects of resistance, epistasis and clonal interference — influence the evolutionary trajectories of drug-resistant clones. We describe commonalities and differences related to resistance development that could guide strategies to improve therapeutic effectiveness and the development of a new generation of drugs.

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“…In these systems perturbations on different time scales, i.e., rare changes in sequence and omnipresent thermal fluctuations, seem very different. Surprisingly, several computational [11][12][13][14] and experimental [15][16][17][18][19] studies suggest a qualitative similarity between the effects of mutations and temperature. Stable proteins are in general more tolerant to point mutations [12,15], and in the case of RNA, the set of structures explored by thermal fluctuations are highly correlated with the minimum free energy structures of single point mutants [11,14].…”

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confidence: 99%

Effective Temperature of Mutations

Derényi

Szöllősi

2015

Phys. Rev. Lett.

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Biological macromolecules experience two seemingly very different types of noise acting on different time scales: i) point mutations corresponding to changes in molecular sequence and ii) thermal fluctuations. Examining the secondary structures of a large number of microRNA precursor sequences and model lattice proteins, we show that the effects of single point mutations are statistically indistinguishable from those of an increase in temperature by a few tens of Kelvins. The existence of such an effective mutational temperature establishes a quantitative connection between robustness to genetic (mutational) and environmental (thermal) perturbations.Biological systems are robust [1], and robustness is considered to be a fundamental feature of complex evolvable systems [2]. Molecular phenotypes, such as stable protein folds and functional RNA structures, have provided fundamental insight into the origin and principles of robustness in biological systems [3][4][5][6][7][8][9][10]. In these systems perturbations on different time scales, i.e., rare changes in sequence and omnipresent thermal fluctuations, seem very different. Surprisingly, several computational [11][12][13][14] and experimental [15][16][17][18][19] studies suggest a qualitative similarity between the effects of mutations and temperature. Stable proteins are in general more tolerant to point mutations [12,15], and in the case of RNA, the set of structures explored by thermal fluctuations are highly correlated with the minimum free energy structures of single point mutants [11,14].The correlation between the effects of point mutations and temperature is less surprising if we recognize that each degree of freedom of the molecule has an average thermal energy of k B T /2 ≈ 2.5/2 kJ/mol (where k B is the Boltzmann constant and T ≈ 300 K is the absolute temperature) and the typical free energy change associated with a point mutation is also of the order of a k B T (approximately 4 kJ/mol for a protein [20], and about twice this large for the breaking of a hydrogen bond in a nucleotide base pair). Despite this similarity in energies, for single instances of the system, i.e., individual copies of protein or RNA molecules, permanent changes in sequence are clearly different from ephemeral thermal kicks. However, the distinction between mutational effects and thermal fluctuations becomes less manifest in large populations and over longer time scales where many possible point mutations are explored as molecules are copied (transcribed and translated) repeatedly via mechanisms prone to errors. From this perspective, perturbations of the phenotype (e.g., the protein fold or RNA secondary structure) resulting from mutations can be expected to have similar effects to thermal perturbations: both jostle the system between structural states with energies that differ by only a few times the thermal energy scale.Here we demonstrate that this qualitative analogy between mutational and thermal perturbations can be taken to a quantitative level, and the effect of point m...

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Origin of Robustness in Generating Drug-Resistant Malaria Parasites

Cited by 43 publications

References 49 publications

Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum

Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum

Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms

Effective Temperature of Mutations

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