Multiple Drugs Compete for Transport via the Plasmodium falciparum Chloroquine Resistance Transporter at Distinct but Interdependent Sites

Bellanca, Sebastiano; Summers, Robert L.; Meyrath, Max; Dave, Anurag; Nash, Megan N.; Dittmer, Martin; Sánchez, Cecilia P.; Stein, Wilfred D.; Martin, R. L.; Lanzer, Michael

doi:10.1074/jbc.m114.614206

Cited by 35 publications

(77 citation statements)

References 50 publications

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“…Another possibility is that the drug competes with a yet to be identified physiological substrate for transport via PfCRT and that this competition impacts on the natural function of the transporter. In this context, it is interesting to note that PfCRT appears capable of simultaneously accepting different substrates at distinct but antagonistically interacting binding sites (Bellanca et al ., ). Binding of two different substrates might result in an inactive transporter or one with substantially reduced activity, depending on the nature of the substrates bound (Bellanca et al ., ).…”

Section: Discussionmentioning

confidence: 97%

“…In this context, it is interesting to note that PfCRT appears capable of simultaneously accepting different substrates at distinct but antagonistically interacting binding sites (Bellanca et al ., ). Binding of two different substrates might result in an inactive transporter or one with substantially reduced activity, depending on the nature of the substrates bound (Bellanca et al ., ). How a geographic PfCRT variant copes with its drug and physiological transport functions is likely determined by its specific amino acid substitutions.…”

Section: Discussionmentioning

confidence: 97%

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Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter

Petersen

Gabryszewski

Johnston

et al. 2015

Molecular Microbiology

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Summary The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter

Petersen

Gabryszewski

Johnston

et al. 2015

Molecular Microbiology

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“…These mutations occur in pfcrt exon 10, which corresponds to amino acid substitutions in transmembrane domain 9. This domain is postulated to function in substrate binding and translocation, similar to transmembrane domain 1, which contains the K76T substitution (20,(22)(23)(24). The functional hypothesis for the regained in vitro CQ susceptibility by acquisition of mutations in exon 10 is the reintroduction of a positive charge (K and R) that would inhibit the binding of CQ and block its extrusion from the digestive vacuole.…”

Section: Discussionmentioning

confidence: 99%

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Moss

Dhingra

Volney

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

131

122

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In regions with high malaria endemicity, the withdrawal of chloroquine (CQ) as first-line treatment of Plasmodium falciparum infections has typically led to the restoration of CQ susceptibility through the reexpansion of the wild-type (WT) allele K76 of the chloroquine resistance transporter gene (pfcrt) at the expense of less fit mutant alleles carrying the CQ resistance (CQR) marker K76T. In low-transmission settings, such as South America, drug resistance mutations can attain 100% prevalence, thereby precluding the return of WT parasites after the complete removal of drug pressure. In French Guiana, despite the fixation of the K76T allele, the prevalence of CQR isolates progressively dropped from >90% to <30% during 17 y after CQ withdrawal in 1995. Using a genome-wide association study with CQ-sensitive (CQS) and CQR isolates, we have identified a single mutation in pfcrt encoding a C350R substitution that is associated with the restoration of CQ susceptibility. Genome editing of the CQR reference strain 7G8 to incorporate PfCRT C350R caused a complete loss of CQR. A retrospective molecular survey on 580 isolates collected from 1997 to 2012 identified all C350R mutant parasites as being CQS. This mutation emerged in 2002 and rapidly spread throughout the P. falciparum population. The C350R allele is also associated with a significant decrease in piperaquine susceptibility in vitro, suggesting that piperaquine pressure in addition to potential fitness costs associated with the 7G8-type CQR pfcrt allele may have selected for this mutation. These findings have important implications for understanding the evolutionary dynamics of antimalarial drug resistance. malaria | drug resistance | evolution | Plasmodium falciparum | PfCRT

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“…10 ist. [290] Diese Ergebnisse führten zur Entwicklung eines 3D-QSAR-Pharmakophormodells zur Chloroquinresistenzinversion und zum ersten sogenannten invertierten Chloroquin 56 (Abbildung 46). Die resultierenden Metabolite sind weniger lipophil, was sich negativ auf die Wirksamkeit gegenüber resistenten P. -falciparum-Stämmen auswirkt.…”

Section: Wirkmechanismus Von Chloroquinunclassified

“…Kürzlich wurde gezeigt, dass Verapamil und Chloroquin teilweise um den Effluxtransport über PfCRT konkurrieren, obwohl sie unterschiedliche und unabhängige Bindungsstellen zu besitzen scheinen. [290] Diese Ergebnisse führten zur Entwicklung eines 3D-QSAR-Pharmakophormodells zur Chloroquinresistenzinversion und zum ersten sogenannten invertierten Chloroquin 56 (Abbildung 46). Diese Verbindung war in vitro gegen Chloroquin-resistente Dd2 P. -falciparum-Stämme aktiv (IC 50 Chloroquin = 102 nm, IC 50 56 = 5.3 nm), aber zu lipophil fürd ie weitere Entwicklung.…”

Section: Wirkmechanismus Von Chloroquinunclassified

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

Agnello¹,

Brand²,

Chellat³

et al. 2019

Angewandte Chemie

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Das natürliche Phänomen der Wirkstoffresistenz stellt eine universelle Beeinträchtigung des Nutzens von pharmazeutischen Wirkstoffen in vielen klinischen Indikationen dar. Antibakterielle und antifungale Wirkstoffe sind dabei ebenso betroffen wie Wirkstoffe zur Behandlung von Krebs, Virusinfektionen oder durch Parasiten hervorgerufene Erkrankungen. Trotz der unterschiedlichen biologischen Zielstrukturen und Organismen, die bei der Entwicklung von Wirkstoffresistenzen involviert sind, konnten grundlegende molekulare Prozesse identifiziert werden, die zum Verständnis des Auftretens von Resistenzen beitragen und die Bekämpfung dieser nachteiligen Mechanismen erlauben. Strukturelle Informationen über die Prinzipien von Wirkstoffresistenzen sind heute vielfältig vorhanden, sodass neue Wirkstoffe entwickelt werden können, die weniger anfällig gegenüber einer Resistenzbildung sein werden. Dieser wissensbasierte Ansatz ist eine Grundlage für den Kampf gegen das unvermeidbare Auftreten von Wirkstoffresistenzen.

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Multiple Drugs Compete for Transport via the Plasmodium falciparum Chloroquine Resistance Transporter at Distinct but Interdependent Sites

Cited by 35 publications

References 50 publications

Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter

Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter

Adaptive evolution of malaria parasites in French Guiana: Reversal of chloroquine resistance by acquisition of a mutation in pfcrt

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

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