University of Birmingham

Start : June 2016 | Status : Active

The scientist: Dr. Alejandro Cabanillas will focus his research on the application of an innovative chemical proteomics ligand–protein capture technology to identify the putative protein targets of different antitubercular drug leads.
Alejandro is a Research fellow at the University of Birmingham with previous experience in cancer drug development under the supervision of Dr. Sam Butterworth. He is an organic chemist by training, and his primary role in this project will be the design, synthesis, and optimisation of linkable analogues of the antitubercular leads for proteomics profiling.

The sponsor: University of Birmingham

Foundation funding: The Foundation is providing £148,782 in support, together with co-funding from the European Unionīs FP7 program through its COFUND scheme.

GSK’s contribution: GSK will contribute its extensive experience in medicinal chemistry and Cellzome´s chemical proteomics platform (Nat Microbiol. 2016, doi:10.1038/nmicrobiol.2015.6).

Project Description: 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.