Mechanistic investigation of resistance via drug-inactivating enzymes in Mycobacterium tuberculosis.

Tuberculosis (TB) is a serious major health concern that has existed from millennia. According to annual WHO report 2016, it is considered as world's ninth highest killer disease by single infectious agent, ranking above HIV/AIDS. To worsen the scenario the development of multi-drug resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB) have significantly reduced the success rate of TB treatment. Several efforts are being made to handle pharmacodynamic resistance (MDR and XDR-TB) involving designing of new inhibitors, targeting mutated target or by multi-targeting agents. However, the issue of pharmacokinetic resistance in TB is not being addressed appropriately till date. Pharmacokinetic mode of resistance involves an intrinsic mechanism of bacterial drug resistance via expression of various enzymes and efflux pumps that are responsible for the loss of activity of the therapeutic agents. Mycobacterium tuberculosis is also intrinsically resistant to various approved agents via pharmacokinetic mechanism of resistance. Several bacterial enzymes are encoded that either degrade or modifies the drugs and renders them ineffective. Targeting such inactivating bacterial enzymes provides a novel approach to make the current therapy effective and combat the problem of resistance. This review provides an insight into different bacterial enzymes which are responsible for pharmacokinetic drug resistance in TB. The structure attributes and mechanism of catalysis employed by these enzymes to inactivate drug have also been discussed which may provide basis for developing novel therapeutic agents for resistant TB.