Function of Resistance Conferring <i>Plasmodium falciparum</i> Chloroquine Resistance Transporter Isoforms

Baro, Nicholas; Callaghan, Paul S.; Roepe, Paul D.

doi:10.1021/bi400557x

Cited by 41 publications

(127 citation statements)

References 42 publications

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“…In resistant strains, the modified transporters are able to remove compound 1 from this vacuole. The mutated PfCRTa have altered amino acids in positions 72 to 76 (CVMNK in the wild type), depending on the geographical origin: CVIET for African and most Southeast Asian resistant strains versus SVMNT for the South American resistant strains (24,25). The hybrid compounds were initially tested in an IC 50 assay, determining the concentration required to inhibit the survival of 50% of parasites.…”

Section: Resultsmentioning

confidence: 99%

Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

Boudhar

Loh

et al. 2016

Antimicrob Agents Chemother

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dResistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.

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Section: Resultsmentioning

confidence: 99%

Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

Boudhar

Loh

et al. 2016

Antimicrob Agents Chemother

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“…However, the existence of CQ-susceptible strains associated with the K76T mutation suggests that other genes could be involved in the resistance to CQ. The 76T mutation is necessary, but not sufficient, for influencing CQ susceptibility (22).…”

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confidence: 99%

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

Wurtz

Fall

Pascual

et al. 2014

Antimicrob Agents Chemother

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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.

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“…2,8 Of the 53 isoforms, 11 are found in culture-adapted strains for which highly reproducible CQ IC 50 data quantifying CQ cytostatic potency are available. 9 However, the remaining isoforms are found in field isolates whose drug susceptibilities are typically determined via more qualitative single-pass assays, or not determined at all.…”

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confidence: 99%

“…9 Initial work with 11 PfCRT isoforms that are expressed in laboratory-cultured P. falciparum strains suggested that PfCRT mutations are necessary but not sufficient for the full shift in CQ IC 50 seen for these strains. 9 To further aid our understanding of the relative contribution of PfCRT isoforms to geographically disposed CQR phenotypes, in this paper we report on 45 of the currently known naturally occurring PfCRT isoforms.…”

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confidence: 99%

Functional Comparison of 45 Naturally Occurring Isoforms of the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT)

2015

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At least 53 distinct isoforms of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein are expressed in strains or isolates of P. falciparum malarial parasites from around the globe. These parasites exhibit a range of sensitivities to chloroquine (CQ) and other drugs. Mutant PfCRT is believed to confer cytostatic CQ resistance (CQRCS) by transporting CQ away from its DV target (free heme released upon hemoglobin digestion). One theory is that variable CQ transport catalyzed by these different PfCRT isoforms is responsible for the range of CQ sensitivities now found for P. falciparum. Alternatively, additional mutations in drug-selected parasites, or additional functions of PfCRT, might complement PfCRT-mediated CQ transport in conferring the range of observed resistance phenotypes. To distinguish between these possibilities, we recently optimized a convenient method for measuring PfCRT-mediated CQ transport, involving heterologous expression in Saccharomyces cerevisiae. Here, we use this method to quantify drug transport activity for 45 of 53 of the naturally occurring PfCRT isoforms. Data show that variable levels of CQR likely depend upon either additional PfCRT functions or additional genetic events, including perhaps changes that influence DV membrane potential. The data also suggest that the common K76T PfCRT mutation that is often used to distinguish a P. falciparum CQR phenotype is not, in and of itself, a fully reliable indicator of CQR status.

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Function of Resistance Conferring Plasmodium falciparum Chloroquine Resistance Transporter Isoforms

Cited by 41 publications

References 42 publications

Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

Overcoming Chloroquine Resistance in Malaria: Design, Synthesis, and Structure-Activity Relationships of Novel Hybrid Compounds

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

Functional Comparison of 45 Naturally Occurring Isoforms of the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT)

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