Oh no! Not another cell wall target [Approaches to TB drug discovery]

In the modern era, there are multiple approaches to drug discovery. For the past decade, H3D, Africa’s first integrated drug discovery centre, has mainly employed phenotypic cell-based screening to identify novel hits against Mycobacterium tuberculosis, and then conduct target elucidation experiments to determine the mechanism of action (MOA). Unfortunately, this method has often led to identifying active series against promiscuous cell wall targets (including cell wall biosynthesis (e.g. MmpL3 and DprE1) and respiratory (e.g. QcrB) mechanisms) that have not been clinically validated for the treatment of tuberculosis. Recently, H3D has shifted tactics to employ target (or structure)-based drug discovery approaches to identify novel hits that target essential enzymes such as RNA polymerase (RNAP) and caseinolytic protease (ClpP).

Both approaches offer significant advantages, but at the same time, distinct challenges. Here, I showcase examples of both approaches from two projects and highlight key findings and learnings.