**7.2 Hurdles in TB drug repurposing**

Development of *in vitro* models for non-replicating and replicating M.tb Bacilli has not been successfully achieved and presents a big challenge in drug discovery. A multi-stress model of non-replication has been put forward [94]. But interpretation of results using this model is difficult due to involvement of outgrowth period [95]. A rapid method not requiring the outgrowth period has been developed to measure bactericidal activity against non-replicating *Mycobacterium tuberculosis*, induced at low pH (citrate buffer at pH 4.5). It can easily detect viable *M. tuberculosis* strain constitutively expressing luciferase [95]. To establish models that represent real metabolic state in various host niches, and the related effects of micro-biome status, nutritional state, and other underlying health issue like diabetes, a significant success is still a dream. So, no screening model can be sufficient enough to bypass extensive follow-on experiments in the human host to ascertain efficacy, pharmacokinetics, pharmacodynamics, toxicity (e.g., specificity), and the mechanism of action to yield better results with more optimization of molecules using medicinal chemistry. In addition to safety concern of the drug, its interaction with other antimicrobial agents is the critical issue to be addressed as the treatment duration

of the disease is long. Ideally, the new drugs are expected to decrease required treatment durations hence improving patient compliance and treatment outcomes. The co-existence of HIV and TB emphasizes that new lead must be compatible with antiretroviral therapy as well as active against resistant forms of TB [96]. Targeting the drug to the site of infection is very long and eventful process, which often makes the compound unable to reach its target in active state at the requisite MIC value for the pathogen [97]. Orally administered drugs are bound to have certain characteristics features for rendering good efficiency. Stability and solubility at the acidic pH, withstanding the first-pass metabolism, adequate lung permeability, uptake by *M. tuberculosis* to reach the intracellular target(s) and chemical stability and activity under pathophysiological conditions some of the features are required for any drug to be repurposed against TB [97–99]. Common challenges of drug repurposing also affect drug reuse against TB. Optimizing selection criteria of target population to evaluate the expected outcome of the drug are one of major challenges. Any error in subject selection can give unexpected adverse results of drug. For example, thalidomide when prescribed for pregnant women in first trimester for managing morning sickness resulted in amelia and phocomelia [100]. Dosing regimen and route of administration are the two important considerations for repurposing of old drug for new indication. The stability of drug formulation is a challenge while optimizing the drug for a new indication [101]. Different physiologies and multiple drug requirements of different patients arise the threat of unexpected adverse events, which mandate the careful investigation of every response upon drug administration. It becomes essential to have data on drug-drug interactions, pharmacodynamics, and pharmacokinetics of the drug prior to its repurposing.
