*6.1. The 'Evolution' of the Anti-TB Drug Pipeline*

The anti-TB drug portfolio went from a 'no treatment' option to a successful therapy in ~20 years. The main properties of drugs in the regimen that was labeled 'Short Course Chemotherapy' were potency against the microbe, the ability to prevent relapse, and compatibility in terms of safety. The next phase, ~1980s, was the search for a compound that could shorten the course of the treatment. In the absence of 'physiologically' relevant in vitro and in vivo models to progress compounds for this property, it was indeed a 'black box' experimentation. However, with the spread of MDR TB, this focus turned to finding compounds 'active on MDR TB' and compatibility with the 'patient comorbidities',

like HIV infection [91]. The concept of introducing 'broad-spectrum antibiotics' for the treatment of TB was a direct consequence of this shift; even the original trial that included 'ofloxacin' into the regimen was for reducing the duration of therapy [25]. Studies in animal models with a combination containing moxifloxacin showed that the combination had a potential to reduce the duration of therapy [92], and this was one of the end points in the trials with moxifloxacin in humans. However, the final results showed that, while the drug was effective, the combination did not reduce the duration of therapy, although it was efficacious on MDR, as well as on DS TB patients. The drug was introduced into the regimen to treat MDR TB [93].

The need for efficacious drugs for treating MDR TB became the 'new end point' for a drug. Both Bedaquiline and Delamanid fulfilled this criterion and are now parts of the new regimen [67,94].

There has been a concerted effort to understand the 'persister' population that is hypothesized to be difficult to eradicate and hence the need for prolonged duration of therapy [95,96]. The non-replicating persister (NRP) state has been the subject of intense investigations and several models representing this state have been developed. Both Bedaquiline and Delamanid are active against MTB bacilli growing under such conditions [16,67]. Further trials to investigate if this property of the new drugs will contribute to the reduction in therapy duration needs to be performed. In parallel, the portfolio is sure to see 'adjunct therapy' compounds that modulate the host response [92–95]. Repurposed candidate drugs offer faster development options and are also expected to enrich the TB portfolio [97–103]. These could also be weapons against the 'persister' population.

#### *6.2. Lead Generation Approaches*

The evolution of the anti-TB drug regimen, including the current portfolio, has followed a traceable pattern of periods. These periods are recognizable by the 'classes' of compounds that were introduced into the regimen. The different lead generation approaches and their accelerators are shown in Figure 8. Accelerators are defined as new knowledge or global exigencies. Each of these accelerators influenced lead generation methodology, to follow a certain approach during a certain period.

**Figure 8.** Evolution of lead generation approaches.

What is the current trend of preclinical 'hit' molecules being identified by using phenotypic screening? Mdluli et al. [104] have discussed this trend which indicates that the majority of these 'hits' act on the targets, namely DprE1, Mmpl3, and Cytochrome bcc complex. This has led to the coining of the term 'promiscuous targets'. The AstraZeneca 'hit' compound list also shows the same trend (Table 3). Why are these targets prone to get hit in phenotypic screens? The ultimate consequence of the so called 'promiscuity' on drug discovery will be fully answered by the clinical trial outcome of the compounds TBA737, BTZ043, PBTZ-169, OPC 167832 (DprE1 and Mmpl3), and Q203 (bcc1 complex) hitting such targets [105].

Another interesting trend is the increased number of compounds in later stages of development that are inhibitors of 'established targets'. This again adds to the concept of 'privileged targets' of MTB (privileged because the inhibition of these targets converts to an antimicrobial effect on MTB). Perhaps the so-called 'promiscuous targets' can also be classified as 'privileged targets'.
