Geographical spread and structural basis of sulfadoxine-pyrimethamine drug-resistant malaria parasites

Chaturvedi, Rini; Chhibber‐Goel, Jyoti; Verma, Ishika; Gopinathan, Sreehari; Parvez, Suhel; Sharma, Amit

doi:10.1016/j.ijpara.2020.12.011

Cited by 23 publications

(15 citation statements)

References 129 publications

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“…Drug resistance causing mutations in the DHPS domain of Plasmodium HPPK-DHPS are well-established [ 26 , 28 , 29 ], and our SNP analysis further confirms the existence of these mutations in the Pf DHPS domain in a majority of the analysed samples; however, the overall mutation frequency for the Pf DHPS domain was found to be only ~4% (Fig. 8 a).…”

Section: Resultssupporting

confidence: 81%

“…Structural mapping of SNPs on Pf HPPK-DHPS shows the presence of the drug resistance-causing mutations in the sulfa drug binding site (Fig. 1 d), as reported earlier [ 29 ]. Moreover, the high occurrence of these mutations in samples confirms the considerable prevalence of Sdx resistance and underscores the importance of global SNP databases as keys to understanding ongoing resistance spread.…”

Section: Resultssupporting

confidence: 79%

“…Field isolate data for the Pf DHPS domain are available from when resistance mutations were already detected in majority of samples; it is difficult to assess whether other non-active site mutations already existed in this domain previous to the introduction of the drug [ 29 , 32 ]. Resistance against antimalarial drugs remains a major concern.…”

Section: Resultsmentioning

confidence: 99%

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Genomic analysis of single nucleotide polymorphisms in malaria parasite drug targets

Gill

Sharma

2022

Parasites Vectors

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Malaria is a life-threatening parasitic disease caused by members of the genus Plasmodium. The development and spread of drug-resistant strains of Plasmodium parasites represent a major challenge to malaria control and elimination programmes. Evaluating genetic polymorphism in a drug target improves our understanding of drug resistance and facilitates drug design. Approximately 450 and 19 whole-genome assemblies of Plasmodium falciparum and Plasmodium vivax, respectively, are currently available, and numerous sequence variations have been found due to the presence of single nucleotide polymorphism (SNP). In the study reported here, we analysed global SNPs in the malaria parasite aminoacyl-tRNA synthetases (aaRSs). Our analysis revealed 3182 unique SNPs in the 20 cytoplasmic P. falciparum aaRSs. Structural mapping of SNPs onto the three-dimensional inhibitor-bound complexes of the three advanced drug targets within aaRSs revealed a remarkably low mutation frequency in the crucial aminoacylation domains, low overall occurrence of mutations across samples and high conservation in drug/substrate binding regions. In contrast to aaRSs, dihydropteroate synthase (DHPS), also a malaria drug target, showed high occurrences of drug resistance-causing mutations. Our results show that it is pivotal to screen potent malaria drug targets against global SNP profiles to assess genetic variances to ensure success in designing drugs against validated targets and tackle drug resistance early on. Graphical Abstract

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Section: Resultssupporting

confidence: 81%

Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

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Genomic analysis of single nucleotide polymorphisms in malaria parasite drug targets

Gill

Sharma

2022

Parasites Vectors

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“…The current malaria treatment involves the use of artemisinin‐based combination (ACT) therapy, chloroquine or sulfadoxine‐pyrimethamine combination therapy. However, the recent surge in antimalarial drug resistance poses a global health threat and impending disease resurgence 1–4 . This threat shall hinder the efforts towards malaria elimination, and emphasizes the need to identify novel drug scaffolds and validated drug targets with newer mechanisms of actions 5,6 .…”

Section: Introductionmentioning

confidence: 99%

“…However, the recent surge in antimalarial drug resistance poses a global health threat and impending disease resurgence. [1][2][3][4] This threat shall hinder the efforts towards malaria elimination, and emphasizes the need to identify novel drug scaffolds and validated drug targets with newer mechanisms of actions. 5,6 However, a dynamic proteome of the plasmodial species makes it difficult to select for multistage targets.…”

Section: Introductionmentioning

confidence: 99%

Structural analyses of the malaria parasite aminoacyl‐tRNA synthetases provide new avenues for antimalarial drug discovery

2021

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Malaria is a parasitic illness caused by the genus Plasmodium from the apicomplexan phylum. Five plasmodial species of P. falciparum (Pf), P. knowlesi, P. malariae, P. ovale, and P. vivax (Pv) are responsible for causing malaria in humans. According to the World Malaria Report 2020, there were 229 million cases and ~ 0.04 million deaths of which 67% were in children below 5 years of age. While more than 3 billion people are at risk of malaria infection globally, antimalarial drugs are their only option for treatment. Antimalarial drug resistance keeps arising periodically and thus threatens the main line of malaria treatment, emphasizing the need to find new alternatives. The availability of whole genomes of P. falciparum and P. vivax has allowed targeting their unexplored plasmodial enzymes for inhibitor development with a focus on multistage targets that are crucial for parasite viability in both the blood and liver stages. Over the past decades, aminoacyl‐tRNA synthetases (aaRSs) have been explored as anti‐bacterial and anti‐fungal drug targets, and more recently (since 2009) aaRSs are also the focus of antimalarial drug targeting. Here, we dissect the structure‐based knowledge of the most advanced three aaRSs—lysyl‐ (KRS), prolyl‐ (PRS), and phenylalanyl‐ (FRS) synthetases in terms of development of antimalarial drugs. These examples showcase the promising potential of this family of enzymes to provide druggable targets that stall protein synthesis upon inhibition and thereby kill malaria parasites selectively.

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Repurposing FDA‐approved drugs to target malaria through inhibition of dihydrofolate reductase in the folate biosynthesis pathway: A prospective approach

Verma,

Chaturvedi,

Lahariya

et al. 2024

J of Cellular Biochemistry

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Dihydrofolate reductase (DHFR) is a ubiquitous enzyme that regulates the biosynthesis of tetrahydrofolate among various species of Plasmodium parasite. It is a validated target of the antifolate drug pyrimethamine (Pyr) in Plasmodium falciparum (Pf), but its clinical efficacy has been hampered due to the emergence of drug resistance. This has made the attempt to screen Food & Drug Administration‐approved drugs against wild‐ and mutant PfDHFR by employing an in‐silico pipeline to identify potent candidates. The current study has followed a virtual screening approach for identifying potential DHFR inhibitors from DrugBank database, based on a structure similarity search of candidates, followed by absorption, distribution, metabolism, and excretion estimation. The screened drugs were subjected to various parameters like docking, molecular mechanics with generalized born and surface area solvation calculations, and molecular simulations. We have thus identified two potential drug candidates, duloxetine and guanethidine, which can be repurposed to be tested for their efficacy against wild type and drug resistant falciparum malaria.

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Geographical spread and structural basis of sulfadoxine-pyrimethamine drug-resistant malaria parasites

Cited by 23 publications

References 129 publications

Genomic analysis of single nucleotide polymorphisms in malaria parasite drug targets

Genomic analysis of single nucleotide polymorphisms in malaria parasite drug targets

Structural analyses of the malaria parasite aminoacyl‐tRNA synthetases provide new avenues for antimalarial drug discovery

Repurposing FDA‐approved drugs to target malaria through inhibition of dihydrofolate reductase in the folate biosynthesis pathway: A prospective approach

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