Principal Investigator (PI)
The Foundation is providing £148,782 in support.
Dr. Alejandro Cabanillas
Leads compounds identified from whole-cell phenotypic screening campaigns provide a privileged starting point for TB drug discovery programmes. The success of this approach, however, relies on efficient strategies for elucidating the cellular targets of these leads. In many instances, target identification rests on the generation of spontaneous drug-resistant mutants, with the expectation that resistance-conferring mutations, revealed by whole-genome sequencing, identifies the protein target of a given hit. However, as resistance can occur through various mechanisms, spontaneous drug-resistant mutations may not only arise in the drug target but also in other cellular proteins that interact with the inhibitor.
A number of structurally diverse lead compounds have been found to generate mutations in the RND family transporter MmpL3, implicating this essential protein as their target. A novel chemical proteomics ligand–protein capture approach has been used to confirm whether or not this was the case for the THPP series (Nat Microbiol. 2016, doi:10.1038/nmicrobiol.2015.6). This study found that this promising class of inhibitor actually targets the cytoplasmic protein EchA6. Some of ‘MmpL3 inhibitors’, identified through whole genome sequencing of spontaneous drug-resistance mutants, may actually act against other protein targets. The aim of this project is to apply the novel chemical proteomics technology, developed by GSK-Cellzome, to other putative MmpL3 inhibitors to confirm whether this is indeed the case.