More than 130 years after Koch’s discovery of Mycobacterium tuberculosis as its etiological agent, tuberculosis (TB) still affects humankind and was responsible for 1.3 million deaths in 2012. This disease reemerged in recent decades as an increasingly important public health problem due to the appearance of multidrug resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains with high mortality rates, the synergy with the HIV/AIDS pandemic and increased poverty. After decades of relative inactivity in TB drug discovery, a promising pipeline of TB drug candidates in different stages of development has emerged recently. In 2012, bedaquiline, the first new TB drug approved since the 1960s, brought new hope for many patients with MDR-TB. Several molecules are now in preclinical studies, phase II and III clinical trials, but the pipeline still needs more novel scaffolds to provide backup drugs given the high attrition rate observed during clinical development. Phenotypic screens have emerged as an efficient means of identifying active compounds for TB drug discovery, especially as almost all hits from target-based screens, which provided potent enzyme inhibitors failed to display useful bactericidal activity against M. tuberculosis.
The Consortium
The MM4TB consortium evolved from the highly successful FP6 project, New Medicines for TB (NM4TB), that delivered a candidate drug for clinical development two years ahead of schedule. Building on these firm foundations and exploiting its proprietary pharmacophores, MM4TB will continue to develop new drugs for TB treatment. An integrated approach will be implemented by a multidisciplinary team that combines some of Europe's leading academic TB researchers with two major pharmaceutical companies and four SMEs, all strongly committed to the discovery of anti-infective agents. MM4TB will use a tripartite screening strategy to discover new hits in libraries of natural products and synthetic compounds, while concentrating on both classical and innovative targets that have been pharmacologically validated. Whole cell screens will be conducted against Mycobacterium tuberculosis using in vitro and ex vivo models for active growth, latency and intracellular infection. Hits that are positive in two or more of these models will then be used for target identification using functional genomics technologies including whole genome sequencing and genetic complementation of resistant mutants, yeast three hybrid, click chemistry and proteomics. Targets thus selected will enter assay development, structure determination, fragment-based and rational drug design programs; functionally related targets will be found using metabolic pathway reconstruction. Innovative techniques, based on microfluidics and array platforms, will be used for hit ranking, determining rates of cidality and confirming mechanism of action. Medicinal chemistry will convert leads to molecules with drug-like properties for evaluation of efficacy in different animal models and late preclinical testing.
TYDOCK PHARMA in collaboration with the partners of the consortium, following a phenotypic screen of a chemical library against replicating M. tuberculosis, found a new family of quinoxalines with antitubercular activity. The lead compound Ty38c is active against extracellular and intracellular M. tuberculosis. The mechanism of resistance to Ty38c and its mechanism of action have been elucidated, and the findings have been validated using biochemical assays and X-ray crystallography. Furthermore, the synthesis and structure activity relationship studies of analogs of Ty38c provide valuable information regarding this novel DprE1 inhibitor.
