Essential redundancies fuel Mycobacterium tuberculosis adaptation to the host

Redundancy in biology is, at a glance, counterintuitive because if the function of two gene products completely overlaps then, throughout the course of evolution, one of the genes will likely accumulate mutations to the point of loss-of-function. The consensus is that partial functional overlap, for example, divergent secondary functions, play a major role in redundancy conservation. This asymmetrical nature offers a crucial advantage: phenotypic plasticity, which ensures that an essential cellular function can adapt to changes in the environment. In this context, the human pathogen Mycobacterium tuberculosis is an interesting example. Despite being an obligate pathogen that has been co-evolving with the human host for millennia, M. tuberculosis genome retains redundant functions at multiple levels that allow the bacilli to adapt to extremely heterogeneous environments in the human host. This review explores how M. tuberculosis functional redundancies mirror the heterogeneity of both intra- and extracellular host niches, with a focus on energy metabolism. Finally, we discuss the challenges and opportunities of functional redundancies in the context of drug development.