Novel pfkelch13 Gene Polymorphism Associates With Artemisinin Resistance in Eastern India

Abstract

Background Artesunate-sulfadoxine-pyrimethamine (ASSP) is the frontline artemisinin combination therapy (ACT) in India. Random, irrational, subtherapeutic artemisinin doses and self-medication with ACT along with predominance of sulfadoxine-pyrimethamine resistance parasite invoked a strong possibility of emerging artemisinin-resistant malaria parasites. Methods This study involved 226 patients with uncomplicated Plasmodium falciparum infection who had successfully completed the 42 days follow-up after ASSP combination therapy from April 2014 to January 2016. We assessed the ASSP treatment efficacy by evaluating parasite clearance half-life, pfkelch13, and other (pfdhfr, pfdhps, pfmdr1, pfcrt) gene mutations and survival of parasites as detected by an ex vivo ring-stage survival assay (RSA). Findings Slow-clearing infections with longer parasite clearance half-lives (>5 hours) were observed in 12% isolates. Cure rate after ASSP treatment was declining to about 84.1%. ASSP failure was recorded in 15.9% (early treatment failure, 7.9%; late treatment failure, 7.9%) of isolates. In sum, 24 patients (10.6%) had parasite clearance half-lives greater than 5 hours with pfkelch13 polymorphism after 441 codon; in 15 of those patients (6.6%), parasites had not cleared by 72 hours after initiation of therapy. Median ex vivo ring-stage survival rate of these isolates was very high (12.2%; 95% confidence interval [CI], 10.9–13.8) from that of cured patients (0.9%; 95% CI, 0.09–1.07). Of these 15 patients, 13 patients had pfkelch13 G625R polymorphism, whereas 2 patients contained R539T polymorphism. As per the World Health Organization guideline, these 15 isolates were true artemisinin-resistant isolates. Interpretation Identification of artemisinin-resistant isolates in India together with new mutations and increasing combination therapy failures blow alarms for urgent malaria control.

Design, Synthesis, Heme Binding and Density Functional Theory Studies of Isoindoline-Dione-4-Aminoquinolines as Potential Antiplasmodials

“…Splitting patterns are indicated as s: singlet, d: doublet, t: triplet, m: multiplet, dd: double doublet, ddd: doublet of a doublet of a doublet and br: broad peak. 13 C NMR spectra were recorded on Bruker 125 MHz and Jeol 100 MHz spectrometers in DMSO-d 6 using TMS as an internal standard. High-resolution mass spectra were recorded on a Bruker-micrOTOF-Q II spectrometer.…”

“…To view the supplementary data that accompany this paper please visit the journal website at: www.futurescience/doi/suppl/10.4155/fmc-2019-0260. Material and methods, Computational methods, density functional theory calculations, Synthesis and spectral data of all the compounds along with scanned 1 H, 13 C, 13 C-DEPT, 1 H-1 H-COSY and 1 H-13 C-HSQC NMR spectra of few representative compounds viz. 4c, 4d, 4f, 4k, 4m, 4o, 4r and 4s are provided in the electronic supplementary information.…”

“…In P. falciparum, the development of resistance to CQ necessitated other therapies and paved the way for the development of artemisinin-based combination therapies, the gold standard for the treatment of falciparum malaria [10]. However, the emergence of artemisinin-tolerant P. falciparum strains in South-East Asia [11] and recently in Eastern India [12,13] is of serious concern. Therefore, novel strategies to address the challenge of antimalarial drug resistance with the development of new drugs are urgently needed [14][15][16][17][18].…”

Sequence Analysis of the K13-Propeller Gene in Artemisinin Challenging Plasmodium falciparum Isolates from Malaria Endemic Areas of Odisha, India: A Molecular Surveillance Study

“…Further continuous reuse of this single ACT resulting in P. falciparum-resistant alleles to Artemisinin or its derivatives has been reported for the first time in Western Cambodia and Thailand border [2,3]; more interestingly, these resistant isolates might be carried by the parasites distributed rapidly across all SE Asian countries and also some parts of Africa [4,5]. Both Artemisinin Combination Therapies (ACTs) and its derivatives along with partner drug resis-tance to P. falciparum isolates have threatened the current efforts for the reduction of the burden of infectious malaria all over the world [6,7] As per the WHO guidelines, the definition of the emerged resistant alleles across Thai and Cambodia border has been characterized by [8,9] not only with reduced parasite clearance rate and increasing parasite clearance halflife or survived young ring stage parasites but also with the continuation of parasites on the third day of ACTs [1,[10][11][12][13][14][15][16][17][18]. These worldwide problems give rise to several approaches for the intense surveillance and detection of Artemisinin-resistant falciparum parasites including molecular marker evaluation [7,19].…”

PfGCN5, a global regulator of stress responsive genes, modulates artemisinin resistance inPlasmodium falciparum

“…This region has historically served as the epicenter for emergence of anti-malarial drug resistance [21–23]. Recent reports from Eastern India have also suggested the presence of artemisinin resistant parasites based on pharmacokinetic and genetic parameters like increased parasite clearance half-life and novel Kelch13 mutations [24, 25].…”