The Whole blood bactericidal activity (WBA) is an ex vivo model for measuring the combined effects of administered drugs, host factors and strain factors on mycobacterial sterilisation. If performed in parallel with PK measurements, the method can be used to evaluate the effect of drugs throughout the dosing cycle. In a group of patients with drug-sensitive TB, WBA correlated with the rate of decline of sputum log colony counts, and was superior in patients whose sputum cultures converted to negative after 8 weeks of treatment.

Whole cell actives identified from a growth inhibition screen are subjected to pathway screens followed by target deconvolution and parallel hit-to-lead.

Growth inhibition screen of fragment libraries followed by PK determinations for efficacy studies.

The human proteasome inhibitor Bortezomib was identified as a potent inhibitor of mycobacterial ClpP in a target mechanism-based whole cell screen. The initial phase of lead optimization aimed to introduce selectivity of the series for the mycobacterial enzyme. A series of novel analogues have been prepared as mycobacterial caseinolytic protease ClpP1P2 inhibitors. Compounds were characterized in a ClpP1P2 target-based cell reporter assay, confirming protease inhibition and bacterial-cell penetration.