Absence of Association between Polymorphisms in the RING E3 Ubiquitin Protein Ligase Gene and Ex Vivo Susceptibility to Conventional Antimalarial Drugs in Plasmodium falciparum Isolates from Dakar, Senegal

Abstract

The RING E3 ubiquitin protein ligase is crucial for facilitating the transfer of ubiquitin. The only polymorphism identified in the E3 ubiquitin protein ligase gene was the D113N mutation (62.5%) but was not significantly associated with the 50% inhibitory concentration (IC 50 ) of conventional antimalarial drugs. However, some mutated isolates (D113N) present a trend of reduced susceptibility to piperaquine (P ‫؍‬ 0.0938). To evaluate the association of D113N polymorphism with susceptibility to antimalarials, more isolates are necessary.

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

“…The difference between clones and field parasites may induce differences between in vitro development of mutations and reduced susceptibility and wild isolates showing different patterns of gene sequence regulation and expression. There was no significant difference in the proportion of parasites with decreased susceptibility to PPQ between the D113 wild-type and the mutated 113N P. falciparum strains in contrary to previous findings [ 16 ].…”

“…Previous studies showed that P. falciparum strains carrying the 113N mutant allele for the E3 ubiquitin-protein ligase gene were less susceptible ex vivo to CQ and DQ, and that all the Senegalese isolates with reduced susceptibility to PPQ were mutants [ 15 , 16 ]. Although the D113N mutation was found in a large number of samples (n = 147, 68.4%), this mutation was not found to be involved in the susceptibility modulation to common anti-malarial drugs.…”

“…Parasite clones were then matched in competition experiments with the drugs and those carrying the mutation out-competed the wild types clones, suggesting the involvement of D113N mutation as a major involvement in ubiquitylation cascade and adaptive response to drug pressure. Another study showed no significant association between the D113N mutation and ex vivo reduced susceptibility to most conventional anti-malarial drugs, except a trend with reduced susceptibility to piperaquine in P. falciparum Senegalese isolates, but the major limitations of this study was the low number of isolates and the geographical provenance of them [ 16 ].…”

Baseline Ex Vivo and Molecular Responses of Plasmodium falciparum Isolates to Piperaquine before Implementation of Dihydroartemisinin-Piperaquine in Senegal

“…All these data suggest that Pfpm2 is not the only gene involved in PPQ resistance in Africa. Other genes must be studied, such as the RING E3 ubiquitin protein ligase gene (42) ex vivo PPQ resistance (44,45), but new mutations in this gene, such as H97Y, F145I, M343L, or G353V, could also be involved (25,35).…”

Malaria, tuberculosis and HIV: what's new? Contribution of the Institut Hospitalo-Universitaire Méditerranée Infection in updated data

“…The IHU-Méditerranée Infection participates in identification, development and/or validation of new molecular resistance markers to doxycycline ( pfmdt and pftetQ ) [59] , [60] , [61] , [62] , quinine ( pfnhe-1 ) [63] , artemisinin ( pfK13 ) [64] , [65] , [66] , [67] , [68] and quinolines ( pfmdr1, pfmdr2, pfmdr5, pfmdr6, etc.) [69] , [70] , [71] , [72] .…”