Genetics and roadblocks of drug resistant tuberculosis

Considering the extensive evolutionary history of Mycobacterium tuberculosis, anti-Tuberculosis (TB) drug therapy exerts a recent selective pressure. However, in a microorganism devoid of horizontal gene transfer and with a strictly clonal populational structure such as M. tuberculosis the usual, but not sole, path to overcome drug susceptibility is through de novo mutations on a relatively strict set of genes. The possible allelic diversity that can be associated with drug resistance through several mechanisms such as target alteration or target overexpression, will dictate how these genes can become associated with drug resistance. The success demonstrated by this pathogenic microbe in this latter process and its ability to spread is currently one of the major obstacles to an effective TB elimination. This article reviews the action mechanism of the more important anti-TB drugs, including bedaquiline and delamanid, along with new findings on specific resistance mechanisms. With the development, validation and endorsement of new in vitro molecular tests for drug resistance, knowledge on these resistance mechanisms and microevolutionary dynamics leading to the emergence and fixation of drug resistance mutations within the host is highly important. Additionally, the fitness toll imposed by resistance development is also herein discussed together with known compensatory mechanisms. By elucidating the possible mechanisms that enable one strain to reacquire the original fitness levels, it will be theoretically possible to make more informed decisions and develop novel strategies that can force M. tuberculosis microevolutionary trajectory down through a path of decreasing fitness levels.