Functions of nitroreductases in mycobacterial physiology and drug susceptibility

Tuberculosis is a respiratory infection that is caused by members of the Mycobacterium tuberculosis complex, with M. tuberculosis (Mtb) being the predominant cause of the disease in humans. The approval of pretomanid and delamanid, two nitroimidazole-based compounds, for the treatment of tuberculosis encourages the development of more nitro-containing drugs that target Mtb. Similar to the nitroimidazoles, many antimycobacterial nitro-containing scaffolds are prodrugs that require reductive activation into metabolites that inhibit the growth of the pathogen. This reductive activation is mediated by mycobacterial nitroreductases, leading to the hypothesis that these nitroreductases contribute to the specificity of the nitro prodrugs for mycobacteria. In addition to their prodrug-activating activities, these nitroreductases have different native activities that support the growth of the bacteria. This review summarizes the activities of different mycobacterial nitroreductases with respect to their activation of different nitro prodrugs and highlights their physiological functions in the bacteria.