**4. Repurposed drugs in discovery**

Numerous ongoing projects are in pre-clinical development across the globe, with collaborative research groups spanning across both industry and academia. Many of these groups form part of the Tuberculosis Drug Accelerator (TBDA) program. Selected repurposed drugs that are currently in pre-clinical development, and which have been assessed *in vitro* or *in vivo* will be discussed further. It is worth noting that several computational screening programs of approved drugs are also ongoing against known targets in *M. tuberculosis.*

#### **4.1 Carprofen and Oxyphenbutazone**

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a class of drugs that are generally used to relieve pain and reduce inflammation, mainly functioning by inhibiting the activity of cyclooxygenase enzymes involved in the regulation of inflammation and blood clotting [19]. In mouse models of TB, the common NSAIDs namely aspirin and ibuprofen were shown to decrease both the size and number of lung lesions and bacillary load as well as improve survival rates [36]. Studies have revealed that analogues in this family namely Carprofen and Oxyphenbutazone were found to exhibit bactericidal activity against mycobacteria through inhibition of mycobacterial drug efflux mechanisms and biofilm growth [19, 36]. Both their antimicrobial and anti-inflammatory properties combined with their low likelihood of adverse effects following administration make them very strong candidates for repurposing as TB treatment.

#### **4.2 Disulfiram**

Disulfiram is a nontoxic drug belonging to the family of Carbamates. It is primarily used to treat chronic alcohol addiction, but has demonstrated potent antimycobacterial activity against clinical isolates, MDR and XDR strains [19, 37]. Moreover, it was demonstrated that the bactericidal activity of Disulfiram is synergistically enhanced in the presence of the metal ion copper, with the mechanism of action of this compound still under investigation [37].
