Dr. Dennis Kyle, distinguished university health professor in the College of Public Health, Department of Global Health, has received an NIH grant for $390,911 to investigate the mechanisms of extreme resistance to antimalarial drugs. The grant from the National Institute of Allergy and Infectious Diseases is for a two-year program of research entitled “Extreme Resistance to Mitochondrial Inhibitors in Plasmodium Falciparum.”
Malaria remains an emerging disease threat because of the prevalence and emergence of multiple drug-resistant parasites that defy the actions of all available antimalarial drugs. Most recently, the problem has been exacerbated by the emergence of resistance to artemisinin, the most important antimalarial drug in the effort to control malaria worldwide. Therefore, it is critical that new drugs be developed to combat this problem.
Of the many potential targets for drug discovery and development, the mitochondrion of the parasite is one of the few validated targets. The mitochondrion is the “power house” of the cell and has been successfully targeted in the past by the antimalarial drug atovaquone. Previous data suggested that a key mutation in cytochrome b of the mitochondrion is responsible for resistance to atovaquone, a drug used in combination with proguanil for treatment and prevention of malaria.
New data from the Kyle Lab demonstrates that atovaquone-resistant parasites have more than just the previously known mutation in the mitochondria genome that can confer resistance to mitochondrial inhibitors. In fact, Kyle has discovered parasites that are resistant to all known inhibitors of the mitochondria, including all the antimalarial drugs in late-stage discovery and development that target the mitochondria.
The focus of the grant is to discover the novel mechanisms of extreme resistance to mitochondrial inhibitors and to use this information to enhance the drug discovery process, as well as to identify drugs or combination partner drugs that can overcome the resistance phenomenon.
The Kyle Lab is a leader in the field of antimalarial drug discovery and resistance mechanisms for malaria. In addition to malaria, the Kyle Lab is working to discover new drugs for the causative agents of visceral leishmaniasis and primary amoebic meningoencephalitis.