**5. Target-based repurposing**

An additional benefit of drug repurposing is the potential to identify or validate vulnerable targets and/or pathways that can be exploited for further drug development [8–10]. Bortezomib is the first human proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma [48]. Using a target mechanism-based whole-cell screen, bortezomib was identified as an inhibitor of the mycobacterial caseinolytic protease (ClpP1P2), with growth inhibitory activity, thus validating it as a druggable target [49]. Further investigations have focused on structural modifications of bortezomib to increase selectivity for the mycobacterial ClpP1P2 complex over the human proteasome while maintaining antimycobacterial activity [49–51]. The *M. tuberculosis* DosRST two-component regulatory system is important for survival under non-replicating conditions which is thought to contribute to the required prolonged therapy for TB, and is therefore considered a promising target for drug development [52]. Artemisinin is used for the treatment of Malaria and was identified as an inhibitor of *M. tuberculosis* DosRST during a whole-cell phenotypic high throughput screen and is currently in the hit-to-lead phase of drug development [52, 53]. In addition to the identification of promising repurposed drugs by whole-cell screening, recent efforts have focused on computational modelling and virtual screening of known drugs against targets of interest. Using this approach two drugs were identified as inhibitors of *M. tuberculosis* DNA gyrase (GyrB): echinacoside which has been investigated for the treatment of Parkinsons and Alzheimers, and epirubicin which is a treatment for breast cancer [54–56]. Virtual screening has also identified Sulfadoxine, Pyrimethamine, Lifitegrast and Silfenadil as inhibitors of *M. tuberculosis* MurB or MurE, enzymes involved in peptidoglycan synthesis [57].
