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They manipulate and hijack phagocytic cells of immune systems, enabling them to occupy this peculiar infection niche. Mycobacteria exploit a plethora of mechanisms to resist antimicrobials (e.\u2009g., waxy cell walls, efflux pumps, target modification, biofilms, etc.) thereby evolving into superbugs, such as extensively drug\u2010resistant tuberculosis (XDR TB) bacilli and the emerging pathogenic <jats:italic>Mycobacterium abscessus<\/jats:italic> complex. This review summarizes the mechanisms of action of some of the surging antimycobacterial strategies. Exploiting the fact that mycobacteria are obligate aerobes and the differences between their oxidative phosphorylation pathways <jats:italic>versus<\/jats:italic> their human counterpart opens a promising avenue for drug discovery. The polymorphism of respiratory complexes across mycobacterial pathogens imposes challenges on the repositioning of antimycobacterial agents to battle the rise in nontuberculous mycobacterial infections. <jats:italic>In silico<\/jats:italic> strategies exploiting mycobacterial respiratory machinery data to design novel therapeutic agents are touched upon. The potential druggability of mycobacterial respiratory elements is reviewed. 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