The Integration of Chemistry and Biology to Seed a Next Generation of Malaria and Tuberculosis Therapeutics
2008-10 Seed Grant
As bacterial resistance to antibiotics becomes more prevalent, the need for pharmacologic agents that combat resistant strains acquires greater urgency. Pleuromutilin is a natural product isolated from edible mushrooms that has been shown to have antibiotic activity against tuberculosis. This natural product has a novel mechanism of action, because its unique core structure allows it to inhibit bacterial ribosomes in a different manner from any known antibiotics. Bacteria are slower to develop resistance to pleuoromutilin than other compounds, and pleuoromutilin has the potential to treat multidrug-resistant (MDR) and extensively-drug resistant (XDR) tuberculosis.
In an effort to increase the potency of the pleuromutilin scaffold, pharmaceutical companies have modified the natural product to develop new antibacterial therapeutics. Although more active derivatives of pleuoromutilin have been discovered by this method, these compounds are rapidly degraded by the liver, which limits their effectiveness.
Sorensen and his team's goal in this project was to identify the minimum scaffold of pleuromutilin necessary for biological activity through a fully synthetic approach, systematically removing parts of the molecule that represent hypothesized metabolic liabilities.
They have developed a concise ten-step synthesis of the core of pleuoromutilin, along the way developing a previously unreported modification of a key reaction that they believe will have broad application for other synthetic chemists. This synthesis allowed them to prepare several derivatives of the core structure of the molecule and test their biological activity.
Emma Yates ’11 has made significant contributions to the pleuromutilin project, which will be a central element in her senior thesis.
With the development of a flexible synthesis of pleuromutilin analogs achieved, the team is ready to prepare compounds with improved biological activity and pharmacokinetic properties. Ultimately, the goal is to find an analog that will be ideal as a therapeutic agent for drug resistant strains of tuberculosis.