Resisting resistance | Nature Reviews Microbiology

ABSTRACT This month's Genome Watch describes how knowledge of the malaria parasite genome can be used to better understand and mitigate the emergence of drug resistance. You have full

access to this article via your institution. Download PDF MAIN The year 2012 marks the tenth anniversary of the publication of the genome sequence for the malaria parasite _Plasmodium

falciparum_1. Over the past decade, thisgenome sequence has been used to support an array of studies ranging from functional work on individual genes to whole-transcriptome analyses. Three

recent studies illustrate how this information can be used to improve our understanding of drug resistance in parasites and to develop early-detection systems that could help to mitigate

emerging drug resistance in endemic areas in the future. One study combined genetic association analyses with high-throughput chemical screening of a pharmaceutical library of 2,816

compounds that are already registered or approved for use in humans or animals2. Screening against 61 lines of _P. falciparum_ identified 32 highly active compounds, some of which had not

previously been reported to have antimalarial activity. Importantly, the study then identified genes associated with the differential drug responses both by analysing the correlation between

single-nucleotide polymorphisms and corresponding drug response phenotypes (a genome-wide association analysis), and by comparing drug response phenotypes to genotypes in the parents and

offspring of two parasite crosses (a genetic-linkage analysis). Remarkably, three genes (_pfcrt_, _pfmdr1_ and _dhfrts_) that are known to be associated with resistance to antimalarial drugs

such as chloroquine, pyrimethamine and mefloquine were revealed to be the dominant genetic loci associated with resistance to a range of compounds. Artemisinin combination therapies are

currently a mainstay of malaria treatment, but resistance is emerging in Southeast Asia. The genetic basis of this resistance was recently studied through the identification of genomic

regions that are under strong selection in three different parasite populations, followed by a targeted association analysis based on a large sample collection from Thailand for which

detailed clinical drug response data was available3. This approach identified a 35 kb region on chromosome 13 that was estimated to cause about one-third of the heritable component of the

reduced drug sensitivity. Intriguingly, the ORF encoding a putative chloroquine resistance marker protein (ORF MAL13P1.380) is located adjacent to this locus, although further work will be

required to identify which of the genes in this locus contribute to the drug resistance phenotype. A further boost to our capacity to understand and monitor malarial drug resistance in

endemic regions has recently been provided by the MalariaGEN (Genomic Epidemiology Network) initiative, which has published its first major population genomics analysis of _P. falciparum_

diversity in natural infections4. By analysing the genome sequences of a large number of parasites, this initiative has added to our understanding ofthepopulation structure, linkage

disequilibrium patterns, and within-host diversity and inbreeding of _P. falciparum_. But the most important contribution of this initiative may be an improved ability to identify those

genes and genomic regions in the malaria parasite that are under the most intense selection in different parts of the world. These selection signatures can reflect the application of drugs

and may point to long existing or newly emerging drug resistance. For example, the different alleles of _pfctr_ and the putative chloroquine resistance marker gene MAL13P1.380, and their

frequencies in different parts of the world, were revealed in the recently published population genomics analysis. One strength of the MalariaGEN research initiative is that it uses a large

volume of data to allow effective correction for population structure and other confounders that may beset any population-wide analysis of _P. falciparum_ and make it difficult to

differentiate the causes behind patterns of genomic variation5. Interrogation of the malaria parasite genome has already taught us some valuable lessons about the ability of this pathogen to

render drugs useless over time. But there is reason to be optimistic that the large-scale application of genome-wide technologies will equip us with the knowledge to use antimalarial drugs

effectively and in a sustainable manner in the future. REFERENCES * Gardner, M. J. et al. Genome sequence of the human malaria parasite _Plasmodium falciparum_. _Nature_ 419, 498–511 (2002).

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AUTHORS AND AFFILIATIONS * Bernardo J. Foth is at the Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. [email protected], Bernardo J. Foth Authors *

Bernardo J. Foth View author publications You can also search for this author inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS The author declares no competing financial

interests. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Foth, B. Resisting resistance. _Nat Rev Microbiol_ 10, 524 (2012).

https://doi.org/10.1038/nrmicro2847 Download citation * Published: 16 July 2012 * Issue Date: August 2012 * DOI: https://doi.org/10.1038/nrmicro2847 SHARE THIS ARTICLE Anyone you share the

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