Manipulation of Bacterial ROS Production Leads to Self-escalating DNA Damage and Resistance-resistant Lethality for Intracellular Mycobacteria

The high prevalence of drug resistance in mycobacteria calls for antimicrobial mechanisms that suppresses the development of resistance. As a structurally conserved multi-site bio-macromolecule, DNA is presumed to be an ideal candidate for such resistance-resistant drug target. However, survey of marketed and investigational DNA interactors indicates that they are not immune to resistance development. Here, we report our strategy to achieve real resistance-resistant DNA targeting by incurring “catastrophic” DNA damage with an organoruthenium-natural product hybrid. The dual-mode DNA damage, in the form of strong tri-valent binding and concomitant oxidative modification, is achieved by manipulating of bacteria’s native endogenous ROS production mechanism upon lethal stress (such as DNA binding). Such self-escalating DNA damage, together with precise targeting of intracellular bacteria via vacuole fusion, thus endows the hybrid’s resistance-resistant lethality against mycobacteria and in vivo efficacy in animal models. ### Competing Interest Statement The authors have declared no competing interest.