*6.3. Has the Pipeline Evolved Based on the Significant Increase in the Knowledge of the 'Biology' of MTB?*

In 1996, Mitchison in his Garrod lecture postulated the presence of different populations of MTB in the lungs of the TB patient [106]. Mitchison postulated the presence of the rapidly multiplying and the slow-growing populations of MTB, as well as the intracellular and extracellular niches of the organism. The last two decades have uncovered several shifts in the physiological state of the pathogen that are responses to both the immune mechanism of the host or the 'niche' in which the pathogen is proliferating [107]. The newer drugs like Bedaquiline, Pretomanid, and Delamanid have been shown to be active against MTB cells in the NRP state in vitro, as well as against the MTB bacilli multiplying within the macrophage [108,109]. However, these drugs were initially identified as inhibitors of the rapidly multiplying pathogen under in vitro culture conditions. It is generally accepted that the MTB population in the human host is a heterogeneous collection of the multiple 'physiological states' [69] that could indeed be a dynamic interchanging state. This raises two questions:


Undoubtedly, there is a rapid expansion in the knowledge of the pathogen biology and its interaction with the host. Additionally, several novel inhibitors for pathways of the host that influence the survival of the bacilli have been identified. However, translational research must be supported to evaluate the potential of these compounds to become anti-TB drugs.
