World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria

Abstract

Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to relate the genetic data to relevant phenotypes. The ongoing replacement of older monotherapies for malaria by new, more effective combination therapies presents an opportunity to create an open access database that brings together standardized data on molecular markers of drug resistant malaria from around the world. This paper presents a rationale for creating a global database of molecular markers for drug resistant malaria and for linking it to similar databases containing results from clinical trials of drug efficacy, in vitro studies of drug susceptibility, and pharmacokinetic studies of antimalarial drugs, in a World Antimalarial Resistance Network (WARN). This database will be a global resource, guiding the selection of first line drugs for treating uncomplicated malaria, for preventing malaria in travelers and for intermittent preventive treatment of malaria in pregnant women, infants and other vulnerable groups. Perhaps most important, a global database for molecular markers of drug resistant malaria will accelerate the identification and validation of markers for resistance to artemisinin-based combination therapies and, thereby, potentially prolong the useful therapeutic lives of these important new drugs.

Single-Nucleotide Polymorphism and Copy Number Variation of the Multidrug Resistance-1 Locus of Plasmodium vivax: Local and Global Patterns

“…Gathering more in vivo, in vitro, and molecular data in a standardized way is expected to aid in the process of validating these and other potential markers of P. vivax drug resistance. 33 Scopel, Raquel Mü ller Gonçalves, Amanda Begosso Gozze, Nathá lia Ferreira Lima, and Vanessa Cristina Nicolete for their support during field work. …”

A Comparison of Methods to Detect and Quantify the Markers of Antimalarial Drug Resistance

“…Despite the interest in using molecular markers to guide policy, [1][2][3] there has been relatively little discussion about the most appropriate way to analyze human blood samples in the context of genetic ambiguity caused by high MOI and misclassification caused by low assay sensitivity. This manuscript addresses these issues.…”

“…These single nucleotide polymorphisms (SNPs) or molecular markers of drug resistance, therefore, have the potential to guide public-health policy in a timely manner. 2,3 Importantly, the optimal way of analyzing these data has never been fully explored, and therefore, it remains a subject of intense debate, particularly for samples originating from the areas of intense malaria transmission that characterize much of sub-Saharan Africa; these areas are where most malaria mortality occurs and where the need for informed drug policy choice is greatest. This manuscript considers the appropriate methods of analyzing and presenting molecular marker data from such areas by evaluating alternative methods of analysis.…”

Towards the Selective Inhibition of Glycolytic Pathway Enzymes: A Computational Analysis of Plasmodium falciparum and Human Triosephosphate Isomerase Ligand Interactions.

“…The decrease in efficiency of current antimalarial agents in many affected regions of the world due to toxic side effects, parasitic resistance and mutation has significantly increased the cost and complexity of curing malaria (Peterson et al, 2011;Bray et al, 2003;Briolant et al, 2010). The limited number of antimalarial drugs, and parasitic resistance to almost every available chemical therapy continues to spur the search for novel, cheaper and better analogues (Plowe et al, 2007;Tony et al, 1997). The molecular mechanism of how some antimalarial drugs exert their antimalarial activity is not completely understood.…”