Malaria and Drug Resistance

Genetically determined variability in drug response by microorganisms is a major clinical problem. Efforts at locating the molecular mechanisms involved in conferring resistant phenotypes have been intensified to delineate the development of resistant phenotypes and ways to combat them.

In malaria infection, treatment of all cases requires the use of an effective antimalarial drug. These include the quinoline based drugs such as quinine and chloroquine, the antifolates and the artemisinin derivatives.

Chloroquine resistant parasites developed early in Asia and South America and later in Africa. This trend led to the use of antifolates as first line drugs in areas where chloroquine resistance predominates, and as a second line drug where chloroquine resistance is now emerging. Current research findings have clearly documented the fast emergence of antifolate resistant parasites in areas where folate is used highly not only as a treatment drug for malaria, but in other microbial infections.

A need for the genetic analysis of the parasite gene that encodes the drug target is necessary to predict ahead of time selectable resistant phenotypes and drugs that could be used to overcome them. To obviate the requirement of culturing the organism for drug sensitivity analysis, the yeast system has provided a simple straight forward aproach to these investigations.

The yeast system enables a knockout of the drug target to be generated. This knockout is then complemented with a heterologous gene for growth and evaluated in the presence of a panel of drugs. Mutant phenotypes are similarly evaluated enabling the prediction of resistant phenotypes and potential drugs that could be used against them. Our present focus is centered on DHPS mutants which either synergistically with DHFR or singularly confer resistance to malaria and other infectious diseases.

Sulfa drugs	Sulfones
Sulfamethoxazole	Dapsone
Sulfadiazine
Sulfathiazole
Sulfadoxine