*Antituberculosis Drug Repurposing: A New Hope for Tackling Multi-Challenging TB in Timely… DOI: http://dx.doi.org/10.5772/intechopen.101642*

**Figure 6.**

*The possible endogenous mechanisms of action of repurposed drugs, and many anti-infectives previously used for other disease indications are being considered for, or are already in various phases of in vitro/in vivo, as well as advanced clinical trial studies [175, 176].*

could be avoided as the resistant mutation in the activating catalase KatG, which is being exhibited by many MDR strains. Chlorpromazine and thioridazine are the members of the phenothiazine class of neuroleptics, and both have been found to inhibit the growth of mycobacteria [79, 166]. Non-steroidal anti-inflammatory drugs (NSAIDs) have been already acclaimed for their anti-inflammatory effects but their antibiotic potential needs further exploration. Structural modifications to improve the antimicrobial activities of NSAIDs such as ibuprofen and carprofen are already ongoing [181]. On the basis of active pharmacophore of celecoxib, analogs that show potent inhibitory activity against *M. tuberculosis* and *S. aureus* have been synthesized and further efforts to optimize these compounds are in progress [182]. The role of aspirin in combination with corticosteroids against TB meningitis has shown to decrease the incidence of strokes and mortality [183]. In a TB treatment, NSAIDs are principally used to mitigate the symptoms that arise from the effects of this prolonged disease and its therapy. In basic animal models, these compounds have already proven pharmacokinetic/dynamic and toxicity profiles, as such there is rational evidence to justify their admittance into early clinical trials. However, the stage of disease and route of administration needs critical consideration for further setting a clinical trial [177]. Compounds with ability to activate or suppress immune system are called immuno-modulators and may be natural or synthesized in origin. These compounds either release pro-inflammatory or anti-inflammatory cytokines to improve the immune response for the efficient killing of the pathogen [184]. To initiate this cascade of events, the pro-inflammatory cytokines are responsible. The immune-modulators act on different immune cells such as lymphocytes, neutrophils, macrophages, natural killer (NK) cells to exert their effector responses aimed at clearing the bacteria from the host. Upon being administered together with the DOTS, immuno-modulators help in the early clearance of the infection and in the prevention of drug-resistance [131]. Some immune-modulators also help in preventing the side effects of the harsh anti-TB antibiotic therapy. WHO has

#### *Antituberculosis Drug Repurposing: A New Hope for Tackling Multi-Challenging TB in Timely… DOI: http://dx.doi.org/10.5772/intechopen.101642*

recommended the inclusion of repurposed drugs such as clofazimine, carbapenems, fluoroquinolones, and linezolid, among many others, for the treatment of drugresistant TB. Among these, clofazimine, being used as part of anti MDR-regimen, is inexpensive and carries a promising ability to be a future TB drug [185]. The pravastatin and statin are still in Phase 2b clinical trials after more than two decades of research on their use as anti-TB agent [186]. But the promising results in mice models motivate to go for further clinical trials. Diclofenac, mainly used to treat arthritis and gout, has recently been used as an antimicrobial drug by *Dutta et al*. and showed its treatment reduced bacterial burden and disease pathogenesis in mice as compared with the control group [187]. Diclofenac also exhibits synergy with streptomycin in mice model of TB [188]. Ibuprofen, like indomethacin, is an undiscriminating –COX inhibitor. Ibuprofen has been reported to promote survival of *M.tb* infected mice while decreasing the number and size of lung lesions because of the low bacterial burden [189]. Byrne et al. have further confirmed that both aspirin and ibuprofen help to shorten the Tb treatment course when used along with the first-line anti-TB drugs [190]. Fluoroquinolones, though well known to exert anti-inflammatory functions, have not been much explored for their immunemodulatory properties in TB. Verampil has shown promising results against TB but there is not sufficient literature study on the effect of verapamil on the immune system. Thus further study is to establish the role of verapamil as an immunemodulator in TB. Significant reduction in the mortality rate in patients receiving both metformin and DOTs treatment has been reported [191, 192]. Metformin affects the number of total white blood cells and neutrophils and with an increase in the ratio of monocytes to lymphocytes in the circulation [193]. Diacon et al. have reported the combinatorial use of amoxicillin/clavulanic acid with carbapenems reduces the *M.tb* burden [194]. But there are scarce reports on the immunological aspects related to the compounds. Therefore, further research is needed for successful repurposing of the drug as antitubercular drug. Sulfadiazine, a leprosy-drug, has been repurposed to treat DR-TB and found to be more efficacious and safe than other anti-TB sulfa drugs [113, 195]. To include such drugs in TB treatment, more trials shall be conducted using random human cohorts as subjects. **Table 1** enlists the drugs in progress for repositioning against TB.

On the basis of reported literature based on bioinformatics, proteomics, and repurposing/repositioning/revival of drugs, it is estimated that bioinformatics and proteomics play a pivotal role in the exploration of diagnostics, therapeutics, and mechanism of resistance against drug resistance tuberculosis. Repurposing is a strategy to handle the grave situation of drug resistance tuberculosis in this era of growing antibiotic resistance. Synergistic effect of repurposed drugs along with the newer anti-TB drugs (bedaquiline and delamanid) is a rising hope for the treatment of MDR-TB, XDR-TB, and TDR-TB.

*Drug Repurposing - Molecular Aspects and Therapeutic Applications*
