NM4TB - New medicines for tuberculosis

EC contribution: : € 11.070.000 (original funding of € 10.870.000, plus € 200.000 from 2006 Targeted Top Up Call)
Duration: : 60 months
Starting date: : 01/01/2006
Funding scheme: : Integrated Project
Keywords: : Mycobacterium tuberculosis; multidrug resistant TB; drug development; signal transduction pathways
Contract/Grant agreement number: : LSHP-CT-2005-018923
Project web-site: : http://www.nm4tb.org

Background:

New Medicines for Tuberculosis (NM4TB) aims to successfully develop new drugs for the treatment of tuberculosis (TB) through an integrated approach implemented by a team that combines some of Europe's leading academic TB researchers with a major pharmaceutical company and three small to medium-sized enterprises (SMEs), all with a strong commitment to discovering new anti-infective agents. NM4TB has a comprehensive portfolio of potential and validated targets, plus several novel, proprietary anti-TB agents in its drug development pipeline. Among the validated targets are several enzymes involved in highly druggable areas such as cell wall biogenesis, nucleic acid synthesis and central metabolic pathways for which assays amenable to high-throughput screening are available. Intensive efforts will focus on rapidly emerging targets that impact upon two as yet untouched areas of the physiology of M. tuberculosis signal transduction pathways and persistence.

Problem:

Tuberculosis (TB) is one of the oldest diseases known to man and has infected one third of the world’s population. As a result, someone dies from the disease every 15 seconds and 30 million more people will lose their lives to TB in the next decade. Although directly observed short-course chemotherapy is available to treat the disease, this treatment is old, slow and inefficient by the current standards of the pharmaceutical industry. Here, the project partners will employ the most innovative approaches to identify and validate targets for new drugs, and implement the screening and medicinal chemistry processes required to identify lead compounds for the generation of candidate drugs.

Aim:

NM4TB aims to successfully develop new drugs for the treatment of TB with the following desired properties:

high potency to reduce treatment duration;
activity against persistent bacilli;
inhibition of new target classes;
activity against multidrug resistant TB;
specificity for Mycobacterium tuberculosis.

Expected and obtained results:

development and implementation of novel enabling technologies required for drug development.
target validation in well-established, 'druggable' areas such as the central metabolism, cell wall and nucleic acid synthesisin addition to more challenging yet highly innovative topics like the signal transduction and persistence mechanisms.
generation of the structural information for as many targets as possible, acting iteratively in the drug development process. Structures of targets with drugs bound to rationally improve drug design.
assay development and screening of deep chemical libraries encompassing 'Active' to 'Hit', 'Hit' to 'Lead' progression; 'lead' optimisation activities that give rise to candidate drugs.

Potential applications:

The proposed research will result in:

the development of new technologies and assays for TB drug development;
the discovery of new classes of lead compounds for fighting TB;
the lead optimisation and progression to candidate drug status.

Coordinator:

Prof. Stewart T. Cole
Unité de Génétique Moléculaire Bactérienne
Institut Pasteur
25-28, rue du Docteur Roux
75724 Paris, France
Tel. +33 145688446
Fax +33 140613583
E-mail: stcole@pasteur.fr

European Commission