**3.1 Tb drug development**

Mid-twentieth century is engraved as golden era in history of antibiotic discovery when streptomycin got discovered and discovery of major classes of antibiotics was initiated using actinomycetes [25, 26]. Decades later, use of semisynthetic compounds as antimicrobials was focused upon as the bugs developed resistance against previous antibiotics [27]. However, Bedaquiline (TMC207), the first FDA approved TB drug for 40 years, was discovered with *Mycobacterium smegmatis* as surrogate but many other good leads are supposed might have been missed in the past [28]. In modern times, the drug development strategy has been updated and two basic approaches are followed *via* phenotypic screening or empirical approach, which involves evaluating the molecule of interest by studying the phenotypic changes it induces in cells, tissues, or whole organisms [29]. The other approach is target-based screening wherein the molecule of interest is screened alongside a precise enzyme *in vitro* [30]. Result of phenotypic screening was small molecule-based drugs that were accepted and approved by FDA between 1999 and 2008 [31]. Consequently, various companies (e.g., Novartis AG and GlaxoSmithKline) and research centers pay attention on phenotypic screening as a considerable device for the process of drug discovery [32]. This approach has been used to screen the inhibition of cell growth [31] and turn out to be successful with clinical-stage anti-TB drugs, such as nitroimidazoles (delamanid and pretomanid) [33], 1,2-diamine SQ-109 [34], and bedaquiline [28]. Two years before, in 2019, this drug discovering approach was approved by FDA for pretomanid for the cure of adults with pulmonary multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) that were non-responsive or treatment-intolerant (www.tballiance.org). Combination of drug Pretomanid along with three-drug linezolid and bedaquiline was approved for 6

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

months, in oral dosage (cooperatively referred to as the BPaL regimen) [35]. But there are certain drawbacks associated with this approach. For example, the high expenditure and ambiguity that is related to phenotypic screening in the process of drug discovery limits its progress in drug development [36]. Target-based approaches are based on the finding effect of drug on certain specific target and are more focused in the preclinical phase of drug development toward the chemical lead optimization and toxicology studies. In 1998, with sequencing of whole *M.tb* genome revealing 4.4 million base pairs and 4000 genes, knowledge about potential *M.tb* targets got broadened and targetbased approach was expected to yield successful results [37]. Target-based screenings have not yielded promising outcomes due to a few reasons such as: (i) permeability of purified enzyme or target to enter screens; (ii) non-specific nature of the molecule to inhibit the target; and (iii) compounds are not constantly effectively bioavailable orally [38]. Likewise, obtaining compounds with cell permeability and without cytotoxicity through medicinal chemistry may be a very time-consuming and intricate process [39]. Target-based approaches need evaluation of target features that include target essentiality, vulnerability, and novelty. A potential target ought to be essential part of fundamental survival or virulence of the pathogen both in active and in latency modes. It shall not be part of human host to avoid toxicity. To evaluate the targets, the essentiality of a target gene is established by mutant generation [40]. To recognize hypothetical proteins as druggable targets in XDR-TB strains, computational subtractive genomics approach has recently been employed [41]. As pointed out by [37], inhibition of ATP Synthase in particular and the energy metabolism are highly druggable targets as confirmed by these findings. To conclude, it is enviable that a three-dimensional structure of a protein target be accessible to help guide medicinal chemistry efforts [42]. By explanation, drug discovery implies exploration of unknown. Though the process of drug discovery might be predisposed by target, all knowledge about the target, a phenotypic product, or precise profile of chemical compound must be screened while selecting molecule for the first time. These, in turn, correspond to biases, which might exert influence on the outcome of choices that are measured as successes, as The "rule of five" put forth by *Lipinski* [43] that is based on the physicochemical profiles of drugs in phase II and the set of rules put forth by Veber [44]. In the process of lead optimization and/or in the process of drug development, improved oral bioavailability in rats serves as guiding principle. ADMET characteristics are enhanced when CLogP <4 and MW <400 Da as recommended by Gleeson [45]. Antimycobacterial drugs/agents do confront rules that are already reputable because they are more lipophilic as recently being reported [46]. The overall drug development process based on phenotypic screening or target specific seems very cumbersome process, and still, successful drug regimen is yet to be achieved. Therefore, approaches of drug repurposing for Tb are essential to be focused upon.
