Hunt Group

Despite the efforts of the scientific community, the world-wide burden of malaria is currently increasing; it now accounts for about 1 million deaths yearly, mostly child mortalities in Africa. Undoubtedly, one major factor has been the catastrophic spread of malaria parasites which are resistant to antimalarial drugs such as chloroquine, pyrimethamine (PYR) and the combination therapy, Fansidar (pyrimethamine + sulfadoxine (S/P)). Presently, artemisinin and its derivatives are increasingly recommended as first-line anti-malarial therapies, particularly in combination with other drugs, such as amodiaquine, piperaquine, mefloquine and S/P. This strategy is used to increase efficacy and to reduce the probability of resistant parasites surviving and spreading.

The past two decades have seen increasing efforts to identify the genetic basis (mutation) of drug resistance phenotypes and the molecular mechanisms of both the drug and the parasites’ resistance response. For instance, mutations in the genes dhfr, dhps, mdr1 and crt have been identified as influencing responses to the drugs pyrimethamine, mefloquine and chloroquine (in some cases, multigenically). Knowledge of these mutations enables us to understand the population dynamics (spread through space and time) of resistant parasites, using genotyping, population genetics and modelling techniques etc. This data is essential if we are to use drugs in the most effective ways.

Concurrently, there is also an increased drive to identify new targets for antimalarial drugs, develop new drugs and ‘revisit’ previously underdeveloped drugs. In the context of all of these factors, it is vital to extend our understanding of how drugs work at a biochemical/metabolic level, how mutations underlying resistance impact upon metabolism and the fitness of the parasite, and how different drugs may interact at the metabolic and genetic level. These questions intrinsically require interdisciplinary and multidisciplinary approaches.

The Hunt group focuses on the following research areas

• Selection of drug resistance mutants in rodent malaria parasites (Plasmodium chabaudi)
• Identification of genetic loci, genes and mutations which underlie drug resistance. At present, we have a particular interest in the resistance to artemisinin and its derivatives (artesunate etc.), chloroquine, Fansidar (pyrimethamine/sulfadoxine combination) and mefloquine.
• Further development of a new genetics strategy called Linkage Group Selection (LGS); experimental, theoretical, statistical
• Development of genome-wide allele quantification markers by pyrosequencing (collaboration with Sandie Cheesman/Richard Carter lab)
• Genomic analysis by genome re-sequencing (Solexa)
• Estimating the fitness costs of drug resistance mutations