No new TB drugs have been brought to the market in the last 30 years. The Global Alliance for TB Drug Development is a driving force in the development of drugs against TB, but their work primarily involves known targets. There is a real need to develop drugs acting in completely new ways on novel targets to combat this disease, otherwise the disease will continue to be spread all over the world. This project aims to develop an arsenal of lead compounds to a selection of new targets that together can be expected to inhibit multiple stages of infection.
Two different strategies will be pursued to inhibit infection of Mycobacterium at multiple stages. One approach targets the bacterial machinery, the other one focuses on the cellular host machinery. The systems selected where drugs might be expected to be active on replicating bacteria include previously untargeted enzymes involved in mycolic acid synthesis, a mainstay of current antibiotics active against tuberculosis, and the ATP synthase, the target of one of the newest anti-TB drugs currently in phase II clinical trials. Completely new targets include the thymidylate synthase ThyX, acyl-CoA carboxylase and members of the UvrD family of DNA helicases, one of which has been implicated in persistence in a mouse infection model suggesting that it may represent a target against latent infection. In a second approach components will be identified that reactivate the phagocytic pathway and induce killing of intracellular pathogens. Since this strategy targets the cellular machinery rather than the pathogen itself, it has the dual advantage of 1) further avoiding the development of multi-resistant bacterial strains and 2) representing a general and outstanding approach applicable to various types of viral and bacterial pathogens.
The ‘one-disease-one-drug-one-target’ paradigm that has dominated thinking in the pharmaceutical industry for the past few decades is now being increasingly challenged by compounds designed to bind more than one target. It is now widely acknowledged that high-specificity for a single target might not always deliver the required efficacy versus side effect profile. Inhibitors that could simultaneously target multiple enzymes may be a novel way to develop ‘multiple ligands’ and could be in tune with the emerging drug discovery paradigm.
Title: New Approaches to Target Tuberculosis
Contract number: 222965
EC contribution: 2.994.478 €
Duration: 36 months
Starting date: 01/10/2008
Instrument: Collaborative project