Start : January 2014 | Status : Complete

The scientists and the sponsor: This project is led by Dr. Simon J. Teague, assisted by Dr. Ian Millichip. The collaboration between TeagueMedChem Ltd and GSK results from world-wide crowdsourcing for new ideas concerning tuberculosis treatment through http://www.innocentive.com. Competitive examination of more than one hundred proposals resulted in selection of this project.

Foundation funding: The Foundation is providing £93,587 in support.

GSK’s contribution: GlaxoSmithKline is providing in-kind contributions including biological evaluation, facilities and expertise from supporting scientists.

Project Description: The project focuses on drug discovery for tuberculosis and is titled “New medicines for tuberculosis through Rifamycin semi-synthesis.” Rifamycin has been the mainstay of tuberculosis combination therapy for more than forty years.

Many antibacterial agents are only bacteriostatic, but Rifamycins are bactericidal. They kill the “persister” bacteria which cause relapse once therapy is stopped and are a key component of DOTS combination therapy. The current limitations of the Rifamycins are Cyp induction, solubility and resistance. Cyp induction results in clinically significant drug-drug interactions, especially for patients who are HIV co-morbid. Almost all known Rifamycin analogues are produced by derivatization of just two positions of the natural product. This derivatization is constrained by synthetic considerations leading to exploration of a very restricted activity and property space. In this project, Rifamycins are subjected to semi-synthesis rather than derivatization. The macrocycle is cleaved in half and entirely new replacements for the naphthoquinone moiety inserted producing novel macrocycles. This may allow for the production of entirely new, designed Rifamycin-like compounds with improved properties and modified resistance profile. The ways in which Rifamycins work has been exhaustively studied over many years. This project attempts to apply this accumulated understanding in the design of new medicines which are useful for treating tuberculosis.