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

Song, J.; Wang, M.; Tao, H.; Yang, A.; Zhu, Z.; Bai, S.; Luo, M.; Xu, J.; Liu, X.; Sun, Y.; Hu, P.; Wong, W.-L.; Li, F.; Chen, Y.; Cai, Q.; Liu, H.; Huang, S.-Y.; Su, Z.; Feng, X.

doi:10.1101/2023.07.07.548098

bioRxiv · 10.1101/2023.07.07.548098

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

Song, J.·Wang, M.·Tao, H.·Yang, A.·Zhu, Z.·Bai, S.·Luo, M.·Xu, J.·Liu, X.·Sun, Y.·Hu, P.·Wong, W.-L.·Li, F.·Chen, Y.·Cai, Q.·Liu, H.·Huang, S.-Y.·Su, Z.·Feng, X.

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Abstract

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 bacterias 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 hybrids resistance-resistant lethality against mycobacteria and in vivo efficacy in animal models.

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Song, J., Wang, M., Tao, H., Yang, A., Zhu, Z., Bai, S., Luo, M., Xu, J., Liu, X., Sun, Y., Hu, P., Wong, W.-L., Li, F., Chen, Y., Cai, Q., Liu, H., Huang, S.-Y., Su, Z., Feng, X.. 2023-07-07. Manipulation of Bacterial ROS Production Leads to Self-escalating DNA Damage and Resistance-resistant Lethality for Intracellular Mycobacteria. https://doi.org/10.1101/2023.07.07.548098

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