Open Collaborative Model for Tuberculosis Lead Optimisation

Early stage Drug Discovery efforts over the last 5 years have resulted in the identification of a number of promising lead compounds in the fight against TB. These leads need to be further progressed and optimised into candidates for pre-clinical development through the Drug Development progression cascade.

Three compound families are of particular interest:
1) InhA Inhibitors,
2) New potent whole cell anti-tubercular compounds with unknown mode of action and
3) new Beta-lactam/Beta-lactamase combinations for TB.

A preclinical package is already in place for some of them, but further work is necessary for others in order to justify the progression of a single anti-tubercular family to the more resource intensive stages of preclinical and clinical development.

The project will encompass the parallel progression of the three compound families through:
A) Lead Optimization Chemistry efforts and MoA studies (Genetic and Proteomic) for whole cell inhibitors,
B) In vitro and in vivo evaluation of a new orally bioavailable Beta-lactam alone or in combination with a Beta-lactamase inhibitor to evaluate the sterilising potential of the new drug/s and
C) the optimization of an InhA inhibitor for later preclinical development.

These efforts will yield candidate molecules for new "information rich" in vitro assays of antimycobacterial activity (artificial granuloma, activity against slow/non growing cells and activity against clinical isolates) as well as for in vivo safety and efficacy evaluation in different animal models of infection (acute and/or chronic).

At this stage a single compound family will be prioritized. Further studies will be performed assessing the potential for shortening treatment in stand alone therapy as well as in combination regimens both in vitro and in vivo. Finally a Clinical Development plan will be put in place for the selected candidate molecule.