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. 2018 Mar 12;17(1):108.
doi: 10.1186/s12936-018-2252-2.

The D113N mutation in the RING E3 ubiquitin protein ligase gene is not associated with ex vivo susceptibility to common anti-malarial drugs in African Plasmodium falciparum isolates

Mathieu Gendrot  1   2 , Francis Tsombeng Foguim  1   2 , Marie Gladys Robert  1   2 , Rémy Amalvict  1   2   3 , Joel Mosnier  1   2   3 , Nicolas Benoit  1   2   3 , Marylin Madamet  1   2   3 , Bruno Pradines  4   5   6 ; French National Reference Centre for Imported Malaria Study Group
Collaborators, Affiliations

The D113N mutation in the RING E3 ubiquitin protein ligase gene is not associated with ex vivo susceptibility to common anti-malarial drugs in African Plasmodium falciparum isolates

Mathieu Gendrot et al. Malar J. .

Abstract

Background: Plasmodium falciparum resistance to artemisinin-based combination therapy has emerged and spread in Southeast Asia. In areas where artemisinin resistance is emerging, the efficacy of combination is now based on partner drugs. In this context, the identification of novel markers of resistance is essential to monitor the emergence and spread of resistance to these partner drugs. The ubiquitylation pathway could be a possible target for anti-malarial compounds and might be involved in resistance. Polymorphisms in the E3 ubiquitin-protein ligase (PF3D7_0627300) gene could be associated with decreased in vitro susceptibility to anti-malarial drugs.

Methods: Plasmodium falciparum isolates were collected from patients hospitalized in France with imported malaria from a malaria-endemic country from January 2015 to December 2016 and, more particularly, from African French-speaking countries. In total, 215 isolates were successfully sequenced for the E3 ubiquitin-protein ligase gene and assessed for ex vivo susceptibility to anti-malarial drugs.

Results: The D113N mutation in the RING E3 ubiquitin-protein ligase gene was present in 147 out of the 215 samples (68.4%). The IC50 values for the ten anti-malarial drugs were not significantly different between the wild-type and mutant parasites (p values between 0.225 and 0.933). There was no significant difference in terms of the percentage of parasites with decreased susceptibility between the D113 wild-type and the 133N mutated P. falciparum strains (p values between 0.541 and 1).

Conclusion: The present data confirmed the absence of the association between polymorphisms in the RING E3 ubiquitin-protein ligase gene and the ex vivo susceptibility to common anti-malarial drugs in African P. falciparum isolates.

Keywords: Anti-malarial drug; In vitro; Malaria; Molecular marker; Plasmodium falciparum; RING E3 ubiquitin-protein ligase gene; Resistance.

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Figures

Fig. 1
Fig. 1
Mechanism of the ubiquitin pathway and the transfer role of the ubiquitin protein ligase E3
Fig. 2
Fig. 2
Dot plot of the IC50 total distribution of each Plasmodium falciparum isolate for chloroquine (CQ), quinine (QN), monodesethylamodiaquine (DQ), mefloquine (MQ), lumefantrine (LMF), piperaquine (PPQ), pyronaridine (PND), dihydroartemisinin (DHA), artesunate (AS) and doxycycline (DOX). Each dot is for an IC50 isolate, blue dots represent the wild D113 isolates and red dots the mutant 113N isolates. The black bar indicates the threshold for parasites with reduced susceptibility
Fig. 3
Fig. 3
Repartition of the D113N mutation per its country of origin. The percentage of the D113N mutation in the E3 ubiquitin protein ligase gene (green to red coloration)
Fig. 4
Fig. 4
Comparison of the prevalences of Plasmodium falciparum isolates with reduced susceptibility to chloroquine (CQ), quinine (QN), monodesethylamodiaquine (DQ), mefloquine (MQ), lumefantrine (LMF), piperaquine (PPQ), pyronaridine (PND), dihydroartemisinin (DHA), artesunate (AS) and doxycycline (DOX) according to the D113N mutation in the E3 ubiquitin protein ligase gene. p values were determined using Fisher’s exact test
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