Article

The evolution of drug-resistant malaria

Howard Hughes Medical Institute, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Transactions of the Royal Society of Tropical Medicine and Hygiene (Impact Factor: 1.93). 04/2009; 103 Suppl 1(1):S11-4. DOI: 10.1016/j.trstmh.2008.11.002
Source: PubMed

ABSTRACT Molecular epidemiological investigations have uncovered the patterns of emergence and global spread of Plasmodium falciparum resistance to chloroquine and sulfadoxine-pyrimethamine. Malaria parasites highly resistant to chloroquine and pyrimethamine spread from Asian origins to Africa, at great cost to human health and life. If artemisinin-resistant falciparum malaria follows the same pattern, renewed efforts to eliminate and eradicate malaria will be gravely threatened. This paper, adapted from a talk given in honour of Professor Malcolm Molyneux in Liverpool in September 2008, reviews the rise and fall of clinically important forms of drug-resistant falciparum malaria and considers how lessons learned from studying the evolution of drug-resistant malaria can be applied to efforts to prevent and deter resistance.

Download full-text

Full-text

Available from: Christopher V Plowe, Aug 25, 2015
0 Followers
 · 
119 Views
  • Source
    • "Drug pressure in the field is also considered to be an essential prerequisite for the development of resistance (Wellems 2002, Plowe 2009). However, the rate at which drug resistance spreads and how the resistant mutants survive in nature are still a matter of investigation (Talisuna et al. 2004, Anderson & Roper 2005, Hyde 2005). Several models, including the degree of drug use, drug elimination half-life, host heterogeneity (Hastings et al. 2002), parasite biomass (Hastings & D'Alessandro 2000), parasite fitness (Walliker et al. 2005), malaria transmission intensity (Hastings & Watkins 2005), host immunity and intrahost dynamics (Hastings 1997), were developed to better understand this drug resistance (Talisuna et al. 2003, 2004, 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The development and rapid spread of chloroquine resistance (CQR) in Plasmodium falciparum have triggered the identification of several genetic target(s) in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76), are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria.
    Memórias do Instituto Oswaldo Cruz 12/2013; 108(8):947-961. DOI:10.1590/0074-0276130274 · 1.57 Impact Factor
  • Source
    • "Still, vaccine development is damped by the partial and temporary nature of naturally acquired protective immunity to malaria [2]. The search for new drugs that fight malaria parasites is of great interest since multi-resistant strains of Plasmodium are already spread worldwide [3]. Another approach that may result in successful treatments is the creation of drug analogs that restores susceptibility to chemotherapy [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: For more than two decades, chloroquine (CQ) was largely and deliberate used as first choice drug for malaria treatment. However, worldwide increasing cases of resistant strains of Plasmodium have hampered its use. Nevertheless, CQ has recently been tested as adjunct therapy in several inflammatory situations, such as rheumatoid arthritis and transplantation procedures, presenting intriguing and promising results. In this review, we discuss recent findings and CQ mechanisms of action vis-à-vis its use as a broad adjunct therapy.
    Immunology letters 07/2013; 153(1). DOI:10.1016/j.imlet.2013.07.004 · 2.37 Impact Factor
  • Source
    • "had tracked the decline in clinical efficacy of pyrimethamine and chloroquine clinical efficacy, but integration of the new tools into the studies opened up important new opportunities. For example, examination of the molecular signatures of resistant alleles of Pfdhfr showed clearly that a single mutation could confer reduced susceptibility to pyrimethamine in vitro, and prolong the time to complete clearance of parasites from the patient (Mendez et al., 2002; Plowe, 2009). However, a mutant allele with two additional mutations had a greater association with clinical failure (Kublin et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The need for robust surveillance of antimalarial drugs is more urgent than it has ever been. In the western region of Cambodia, artemisinin resistance has emerged in Plasmodium falciparum and threatens to undermine the efficacy of highly effective artemisinin combination therapies. Although some manfestations of artemisinin tolerance are unique to this class of drug, many of its properties mirror previous experience in understanding and tracking resistance to other antimalarials. In this review we outline the spectrum of approaches that were developed to understand the evolution and spread of antifolate resistance, highlighting the importance of integrating information from different methodologies towards a better understanding of the underlying biologic processes. We consider how to apply our experience in investigating and attempting to contain antifolate resistance to inform our prospective assessment of novel antimalarial resistance patterns and their subsequent spread.
    12/2012; 2:126–133. DOI:10.1016/j.ijpddr.2012.03.004
Show more