Multidrug Resistance-Associated Proteins

Publication Title: 
PloS One

Chemotherapy is a critical component of malaria control. However, the most deadly malaria pathogen, Plasmodium falciparum, has repeatedly mounted resistance against a series of antimalarial drugs used in the last decades. Southeast Asia is an epicenter of emerging antimalarial drug resistance, including recent resistance to the artemisinins, the core component of all recommended antimalarial combination therapies. Alterations in the parasitic membrane proteins Pgh-1, PfCRT and PfMRP1 are believed to be major contributors to resistance through decreasing intracellular drug accumulation.

Author(s): 
Veiga, Maria Isabel
Ferreira, Pedro Eduardo
Jörnhagen, Louise
Malmberg, Maja
Kone, Aminatou
Schmidt, Berit Aydin
Petzold, Max
Björkman, Anders
Nosten, François
Gil, José Pedro
Publication Title: 
Antimicrobial Agents and Chemotherapy

Multidrug-resistant Plasmodium falciparum malaria parasites pose a threat to effective drug control, even to artemisinin-based combination therapies (ACTs). Here we used linkage group selection and Solexa whole-genome resequencing to investigate the genetic basis of resistance to component drugs of ACTs. Using the rodent malaria parasite P. chabaudi, we analyzed the uncloned progeny of a genetic backcross between the mefloquine-, lumefantrine-, and artemisinin-resistant mutant AS-15MF and a genetically distinct sensitive clone, AJ, following drug treatment.

Author(s): 
Borges, Sofia
Cravo, Pedro
Creasey, Alison
Fawcett, Richard
Modrzynska, Katarzyna
Rodrigues, Louise
Martinelli, Axel
Hunt, Paul
Publication Title: 
Malaria Journal

BACKGROUND: In 2005, Ghana replaced chloroquine with artemisinin-based combination therapy as the first-line treatment for uncomplicated malaria. The aim of this work was to determine for the first time, polymorphisms in the putative pfATPase6 and pftctp, pfmdr1, pfcrt genes in Ghanaian isolates, particularly at a time when there is no report on artemisinin resistance in malaria parasites from Ghana. The sensitivity of parasite isolates to anti-malaria drugs were also evaluated for a possible association with polymorphisms in these genes.

Author(s): 
Kwansa-Bentum, Bethel
Ayi, Irene
Suzuki, Takashi
Otchere, Joseph
Kumagai, Takashi
Anyan, William K.
Osei, Joseph H. N.
Asahi, Hiroko
Ofori, Michael F.
Akao, Nobuaki
Wilson, Michael D.
Boakye, Daniel A.
Ohta, Nobuo
Publication Title: 
Antimicrobial Agents and Chemotherapy

Molecular markers for surveillance of Plasmodium falciparum resistance to current antimalarials are sorely needed. A 28-day efficacy study of artemether-lumefantrine in eastern Sudan identified 5 treatment failures among 100 evaluable patients; 9 further individuals were parasite positive by PCR during follow-up. Polymorphisms in pfatpase6 and pfmdr1 were evaluated by DNA sequencing. One individual carried parasites with a novel pfmdr1 polymorphism (F1044L).

Author(s): 
Gadalla, Nahla B.
Adam, Ishag
Elzaki, Salah-Eldin
Bashir, Sahar
Mukhtar, Izdihar
Oguike, Mary
Gadalla, Amal
Mansour, Fathi
Warhurst, David
El-Sayed, Badria B.
Sutherland, Colin J.
Publication Title: 
Acta Tropica

Amodiaquine (AQ) is currently being used as a partner drug in combination with artesunate for treatment of uncomplicated malaria in most endemic countries of Africa. In the absence of molecular markers of artemisinin resistance, molecular markers of resistance to AQ may be useful for monitoring the development and spread of parasites resistance to Artesunate-Amodiaquine combination.

Author(s): 
Folarin, O. A.
Bustamante, C.
Gbotosho, G. O.
Sowunmi, A.
Zalis, M. G.
Oduola, A. M. J.
Happi, C. T.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Emergence of artemisinin resistance in Cambodia highlights the importance of characterizing resistance to this class of drugs. Previously, intermediate levels of resistance in Plasmodium falciparum were generated in vitro for artelinic acid (AL) and artemisinin (QHS). Here we expanded on earlier selection efforts to produce levels of clinically relevant concentrations, and the resulting lines were characterized genotypically and phenotypically. Recrudescence assays determined the ability of resistant and parent lines to recover following exposure to clinically relevant levels of drugs.

Author(s): 
Tucker, Matthew S.
Mutka, Tina
Sparks, Kansas
Patel, Janus
Kyle, Dennis E.
Publication Title: 
Antimicrobial Agents and Chemotherapy

Analysis of the evolution of drug target genes under changing drug policy is needed to assist monitoring of Plasmodium falciparum drug resistance in the field. Here we genotype Pfcrt and Pfdmr1 of 700 isolates collected in French Guiana from 2000 (5 years after withdrawal of chloroquine) to 2008, i.e., the period when the artemether-lumefantrine combination was progressively introduced and mefloquine was abandoned. Gene sequencing showed fixation of the 7G8-type Pfcrt SMVNT resistance haplotype and near fixation of the NYCDY Pfdmr1 haplotype.

Author(s): 
Legrand, Eric
Yrinesi, Joséphine
Ekala, Marie-Thérèse
Péneau, Julie
Volney, Béatrice
Berger, Franck
Bouchier, Christiane
Bertani, Stéphane
Musset, Lise
Meynard, Jean-Baptiste
Mercereau-Puijalon, Odile
Publication Title: 
The American Journal of Tropical Medicine and Hygiene

The effect of antimalarial drug selection on pfcrt and pfmdr1 polymorphisms in Plasmodium falciparum isolates from two distinct geographical locations was determined in 70 and 18 P. falciparum isolates from Nigeria and Brazil, respectively, using nested polymerase chain reaction and direct DNA sequencing approaches. All isolates from Brazil and 72% from Nigeria harbored the mutant SVMNT and CVIET pfcrt haplotype, respectively. The pfcrt CVMNT haplotype was also observed in (7%) of the Nigerian samples.

Author(s): 
Gbotosho, Grace O.
Folarin, Onikepe A.
Bustamante, Carolina
da Silva, Luis Hildebrando Pereira
Mesquita, Elieth
Sowunmi, Akintunde
Zalis, Mariano G.
Oduola, Ayoade M. J.
Happi, Christian T.
Publication Title: 
Malaria Journal

BACKGROUND: Drug resistance is a major problem to control Plasmodium falciparum infection in endemic countries. During last decade, African countries have changed first-line treatment to artemisinin-based combinations therapy (ACT); sulphadoxine-pyrimethamine (SP) is recommended for Intermittent Preventive Therapy (IPT). Molecular markers related to P falciparum resistance were analysed for the period of transition from SP to ACT, in isolates imported from Africa.

Author(s): 
Amor, Aranzazu
Toro, Carlos
Fernández-Martínez, Amalia
Baquero, Margarita
Benito, Agustín
Berzosa, Pedro
Publication Title: 
Malaria Journal

BACKGROUND: Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ), previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ) monotherapy.

Author(s): 
Menard, Sandie
Morlais, Isabelle
Tahar, Rachida
Sayang, Collins
Mayengue, Pembe Issamou
Iriart, Xavier
Benoit-Vical, Françoise
Lemen, Brigitte
Magnaval, Jean-François
Awono-Ambene, Parfait
Basco, Leonardo K.
Berry, Antoine

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