Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

Abstract

The involvement of Pfmdr1 (Plasmodium falciparum multidrug resistance 1) polymorphisms in antimalarial drug resistance is still debated. Here, we evaluate the association between polymorphisms in Pfmdr1 (N86Y, Y184F, S1034C, N1042D, and D1246Y) and Pfcrt (K76T) and in vitro responses to chloroquine (CQ), mefloquine (MQ), lumefantrine (LMF), quinine (QN), monodesethylamodiaquine (MDAQ), and dihydroartemisinin (DHA) in 174 Plasmodium falciparum isolates from Dakar, Senegal. The Pfmdr1 86Y mutation was identified in 14.9% of the samples, and the 184F mutation was identified in 71.8% of the isolates. No 1034C, 1042N, or 1246Y mutations were detected. The Pfmdr1 86Y mutation was significantly associated with increased susceptibility to MDAQ (P ‫؍‬ 0.0023), LMF (P ‫؍‬ 0.0001), DHA (P ‫؍‬ 0.0387), and MQ (P ‫؍‬ 0.00002). The N86Y mutation was not associated with CQ (P ‫؍‬ 0.214) or QN (P ‫؍‬ 0.287) responses. The Pfmdr1 184F mutation was not associated with various susceptibility responses to the 6 antimalarial drugs (P ‫؍‬ 0.168 for CQ, 0.778 for MDAQ, 0.324 for LMF, 0.961 for DHA, 0.084 for QN, and 0.298 for MQ). The Pfmdr1 86Y-Y184 haplotype was significantly associated with increased susceptibility to MDAQ (P ‫؍‬ 0.0136), LMF (P ‫؍‬ 0.0019), and MQ (P ‫؍‬ 0.0001). The additional Pfmdr1 86Y mutation increased significantly the in vitro susceptibility to MDAQ (P < 0.0001), LMF (P < 0.0001), MQ (P < 0.0001), and QN (P ‫؍‬ 0.0026) in wild-type Pfcrt K76 parasites. The additional Pfmdr1 86Y mutation significantly increased the in vitro susceptibility to CQ (P ‫؍‬ 0.0179) in Pfcrt 76T CQ-resistant parasites.

K13 Propeller Alleles, mdr1 Polymorphism, and Drug Effectiveness at Day 3 after Artemether-Lumefantrine Treatment for Plasmodium falciparum Malaria in Colombia, 2014-2015

“…We also found that 98.3% of our samples carried the 184F mutation, similarly to the 92.8% and 100% prevalences reported for Colombian Pacific Coast samples (32) and Brazilian samples (38). The relationship between the 184F mutation and antimalarial drug responses is unclear, as it has been associated with decreased in vitro susceptibility to MQ, HF, and quinine (QN) in some studies (37,40) but not in others (37,41). In Senegal, however, the single mutant 86Y-Y184 haplotype-which was rare in our study-has been significantly associated with increased in vitro susceptibility to AQ, MQ, and LF (41).…”

“…The relationship between the 184F mutation and antimalarial drug responses is unclear, as it has been associated with decreased in vitro susceptibility to MQ, HF, and quinine (QN) in some studies (37,40) but not in others (37,41). In Senegal, however, the single mutant 86Y-Y184 haplotype-which was rare in our study-has been significantly associated with increased in vitro susceptibility to AQ, MQ, and LF (41). It is possible that the N86-184F haplotype that we commonly identified in our samples, which has been associated with decreased susceptibility to LF, MQ, QN, and piperaquine (37), has been selected over the drugsusceptible 86Y-184Y haplotype.…”

Analysis of anti-malarial resistance markers in pfmdr1 and pfcrt across Southeast Asia in the Tracking Resistance to Artemisinin Collaboration

“…Y184F polymorphism was most common, especially in western Cambodia and eastern Thailand, and WGS data also revealed other pfmdr1 mutations (e.g., the F1226Y mutation prevalent in Mae Sot). Both of these mutations have been associated with decreased in vitro susceptibility to mefloquine [51, 52], although most studies have not found Y184F to be significantly associated with changes in drug responses [53, 54]. Further studies are needed to determine whether these mutations are being naturally selected for drug resistance or other phenotypes.…”

Genetic polymorphisms in Plasmodium falciparum chloroquine resistance genes, pfcrt and pfmdr1, in North Sulawesi, Indonesia

“…However, the reported prevalence rates in Peninsular Malaysia (5.3%, p  = 0.000), Cambodia (2.15%, p  = 0.000), western Thailand (3.1%, p  = 0.000), and the upper southern part of Thailand (36.4%, p  = 0.000) differed from ours [19, 33–36]. Other studies have described almost equal prevalence rates for pfmdr1 86Y in African countries such as Kenya (81.6%, p  = 0.545) or even lower prevalence in Benin (57.1%, p  = 0.000), Malawi (22.7%, p  = 0.000), and Senegal (14.9%, p  = 0.000) [13, 14, 30, 37]. Note that one of the lowest prevalence rates for the mutant genotype 86Y was reported from Malawi, where the prevalence of the mutant pfcrt also decreased dramatically [16, 30].…”