Analysis of the PfCRT K76T Mutation in<i>Plasmodium falciparum</i>Isolates from the Amazon Region of Brazil

Vieira, Pedro-Paulo; Alecrim, Maria das Graças Costa; Silva, Luiz H. P. da; González-Jiménez, Iveth; Zalis, Mariano

doi:10.1086/320739

Cited by 32 publications

(33 citation statements)

References 6 publications

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“…In some parts of south-east Asia and most of South America, polymorphisms associated with resistance in one or both these genes are near-ubiquitous (Povoa et al, 1998;Zalis et al, 1998;Labbe et al, 2001;Vieira et al, 2001;Contreras et al, 2002;Cortese et al, 2002;Lopes et al, 2002;Vinayak et al, 2003;Casey et al, 2004;Huaman et al, 2004;Vathsala et al, 2004), a situation attributed to relatively higher levels of symptomatic infections and consequently increased levels of drug usage (Warhurst and Duraisingh, 2001;Hastings, 2003). In such circumstances, cessation of CQ use would not automatically lead to an expanded population of parasites carrying the wildtype alleles as the possibility of mixed infections, and thus competition between resistant and sensitive parasites, would be minimal.…”

Section: Discussionmentioning

confidence: 99%

“…In isolates from most areas of the world where falciparum malaria is endemic, there is typically a positive correlation between mutations in either or both these genes, and in vitro CQ resistance (Foote et al ., 1990;Zalis et al ., 1998;Duraisingh et al ., 2000a;Babiker et al ., 2001;Durand et al ., 2001;Vieira et al ., 2001;Chen et al ., 2003;Lim et al ., 2003;Pickard et al ., 2003). However, with the identification of at least four different foci of emergence of CQ resistance (Wootton et al ., 2002), the genetic basis of resistance to CQ may well vary in different geographical regions, albeit with strong tendencies for convergence at the pfmdr1 and pfcrt loci.…”

Section: Introductionmentioning

confidence: 99%

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pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

Hayward

Saliba

Kirk

2005

Molecular Microbiology

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SummaryEfforts to control malaria worldwide have been hindered by the development and expansion of parasite populations resistant to many first-line antimalarial compounds. Two of the best-characterized determinants of drug resistance in the human malaria parasite Plasmodium falciparum are pfmdr1 and pfcrt , although the mechanisms by which resistance is mediated by these genes is still not clear. In order to determine whether mutations in pfmdr1 associated with chloroquine resistance affect the capacity of the parasite to persist when drug pressure is removed, we conducted competition experiments between P. falciparum strains in which the endogenous pfmdr1 locus was modified by allelic exchange. In the absence of selective pressure, the component of chloroquine resistance attributable to mutations at codons 1034, 1042 and 1246 in the pfmdr1 gene also gave rise to a substantial fitness cost in the intraerythrocytic asexual stage of the parasite. The loss of fitness incurred by these mutations was calculated to be 25% with respect to an otherwise genetically identical strain in which wild-type polymorphisms had been substituted at these three codons. At least part of the fitness loss may be attributed to a diminished merozoite viability. These in vitro results support recent in vivo observations that in several countries where chloroquine use has been suspended because of widespread resistance, sensitive strains are re-emerging.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

Hayward

Saliba

Kirk

2005

Molecular Microbiology

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“…Such indices consistently gave a stable value of 2 to 3 for several sites or different years (54), indicating that the prevalence of clinical or parasitologic failure was two to three times lower than the prevalence of the gene mutation. The association of the pfcrt codon 76 mutations with in vivo CQ treatment failure has been observed in several settings (13,21,39,61,127,164,214) but not in others (57,111), especially in areas where CQ resistance was very high. In these situations, the GRI and GFI might not predict CQ treatment failure because the prevalence of the gene mutation in these populations has reached a plateau (111).…”

Section: Methods For Monitoring Parasite Resistancementioning

confidence: 99%

History, Dynamics, and Public Health Importance of Malaria Parasite Resistance

2004

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Despite considerable efforts, malaria is still one of the most devastating infectious diseases in the tropics. The rapid spread of antimalarial drug resistance currently compounds this grim picture. In this paper, we review the history of antimalarial drug resistance and the methods for monitoring it and assess the current magnitude and burden of parasite resistance to two commonly used drugs: chloroquine and sulfadoxine-pyrimethamine. Furthermore, we review the factors involved in the emergence and spread of drug resistance and highlight its public health importance. Finally, we discuss ways of dealing with such a problem by using combination therapy and suggest some of the research themes needing urgent answers

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“…In the Brazilian Amazon, 1.6 million positive plates (thick smears) in a total of 8 million diagnostic tests for malaria were registered from January 2004 to February 2007 (Ministério da Saúde, Sivep-Malaria 2007). The lack of an effective vaccine and the increasing expansion of strains of Plasmodium falciparum presenting resistance towards commonly used, low-cost antimalarials make control of this disease difficult (Olliaro & Bloland 2001, Wellens & Plowe 2001, Vieira et al 2001, Gonzales et al 2003, Alecrim et al 2006. As a result, the World Health Organization (WHO 1978(WHO , 1995 has been promoting research on natural product based drugs for treatment of disease and many plant species have been evaluated for antimalarial activity (Weniger et al 2004).…”

Section: This Is Also the First Report On The Isolation Of Aspidocarpmentioning

confidence: 99%

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

Andrade‐Neto

Pohlit

Pinto

et al. 2007

Mem. Inst. Oswaldo Cruz

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In the present study, a quassinoid, neosergeolide, isolated from the roots and stems of Picrolemma sprucei (Simaroubaceae), the indole alkaloids ellipticine and aspidocarpine, isolated from the bark of Aspidosperma vargasii and A. desmanthum (Apocynaceae), respectively, and 4-nerolidylcatechol, isolated from the roots of Pothomorphe peltata (Piperaceae), all presented significant in vitro inhibition (more active than quinine and chloroquine) of the multi-drug resistant K1 strain of Plasmodium falciparum. Neosergeolide presented activity in the nanomolar range. This is the first report on the antimalarial activity of these known, natural compounds. This is also the first report on the isolation of aspidocarpine from A. desmanthum. These compounds are good candidates for pre-clinical tests as novel lead structures with the aim of finding new antimalarial prototypes and lend support to the traditional use of the plants from which these compounds are derived.Key words: neosergeolide -ellipticine -aspidocarpine -4-nerolidylcatechol -Pothomorphe peltata -Picrolemma spruceiAspidosperma spp.Malaria is the main cause of economic loss and high morbidity in the world today and continues to be endemic to tropical regions such as the Amazon. In the Brazilian Amazon, 1.6 million positive plates (thick smears) in a total of 8 million diagnostic tests for malaria were registered from January 2004 to February 2007 (Ministério da Saúde, Sivep-Malaria 2007). The lack of an effective vaccine and the increasing expansion of strains of Plasmodium falciparum presenting resistance towards commonly used, low-cost antimalarials make control of this disease difficult (Olliaro & Bloland 2001, Wellens & Plowe 2001, Vieira et al. 2001, Gonzales et al. 2003, Alecrim et al. 2006. As a result, the World Health Organization (WHO 1978(WHO , 1995 has been promoting research on natural product based drugs for treatment of disease and many plant species have been evaluated for antimalarial activity (Weniger et al. 2004). In these studies, emphasis has been on the discovery of lead compounds for drug development (Gundidza & Chinyanganya 1999). The rational search for active substances in medicinal plants is a very promising and cost-effective strategy for antimalarial drug discovery. This approach benefits from the accumulated knowledge of the curing capacity of plants possessed by inhabitants of malaria endemic regions and permits the extensive evaluation of natural products derived from these sources (Campbell et al. 1997, 1998, Brandão et al. 1992, 1997, Krettli et al. 2001, Andrade-Neto et al. 2004a.This triage of useful and effective plants is at the heart of traditional medicinal knowledge and is an extremely important source of therapeutic compounds in use today. Important semi-synthetic, low-cost, highly effective antimalarial drugs such as the quinolines (chloroquine, mefloquine, primaquine, etc.) and artemisinin derivatives (sodium artesunate, arteether, artemether, etc.) owe their initial discovery to the isolation and structural identi...

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Analysis of the PfCRT K76T Mutation inPlasmodium falciparumIsolates from the Amazon Region of Brazil

Cited by 32 publications

References 6 publications

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

History, Dynamics, and Public Health Importance of Malaria Parasite Resistance

In vitro inhibition of Plasmodium falciparum by substances isolated from Amazonian antimalarial plants

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