Principal Investigator (PI)
The Foundation is providing £135,680 in support.
Dr. Abraham Lopez
The phenotypic approach for the discovery of new anti-TB drugs relies on the screening of compound libraries against Mtb in in-vitro artificial growth conditions. However, those conditions do not resemble the physiological environment in human macrophages, which is one of the hallmarks of Mtb pathogenesis. The group of Prof. Av-Gay has recently carried out a TCOLF-funded HTS against Mtb-infected human macrophages. This activity led to promising identified hits, showing inhibition of bacteria growth at low micromolar concentrations with a remarkable 2 orders of magnitude increase in intra-macrophage activity compared to the in-vitro whole cell assay. The initial stage of this program will involve early stage in-vitro TB biology and ADMET profiling of selected hits. Initial synthetic efforts will focus on a limited set of target compounds to define the minimum pharmacophore, identify issues and demonstrate the scope for a more extensive hit to lead (H2L) plan to address the issues. The H2L process typically requires a number of synthesis rounds (≈50 compounds). In order to enter lead optimization, the series should be significantly de-risked, demonstrated in-vivo efficacy and have a suitable probability of delivering an optimized lead compound. In addition to this work, a detailed study on the mechanism of action will be carried out in parallel, potentially leading to the discovery of a novel drug target for TB.