| Summary: | Occurrence of non-canonical G-quadruplex (G4) DNA structures in the genome have been recognized as key factors in gene regulation and several other cellular processes. The <i>mosR</i> and <i>ndhA genes</i> involved in pathways of oxidation sensing regulation and ATP generation, respectively, make <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) bacteria responsible for oxidative stress inside host macrophage cells. Circular Dichroism spectra demonstrate stable hybrid G4 DNA conformations of <i>mosR</i>/<i>ndhA</i> DNA sequences. Real-time binding of mitoxantrone to G4 DNA with an affinity constant ~10<sup>5</sup>–10<sup>7</sup> M<sup>−1</sup>, leads to hypochromism with a red shift of ~18 nm, followed by hyperchromism in the absorption spectra. The corresponding fluorescence is quenched with a red shift ~15 nm followed by an increase in intensity. A change in conformation of the G4 DNA accompanies the formation of multiple stoichiometric complexes with a dual binding mode. The external binding of mitoxantrone with a partial stacking with G-quartets and/or groove binding induces significant thermal stabilization, ~20–29 °C in <i>ndhA/mosR</i> G4 DNA. The interaction leads to a two/four-fold downregulation of transcriptomes of <i>mosR</i>/<i>ndhA</i> genes apart from the suppression of DNA replication by <i>Taq</i> polymerase enzyme, establishing the role of mitoxantrone in targeting G4 DNA, as an alternate strategy for effective anti-tuberculosis action in view of deadly multi-drug resistant tuberculosis disease causing bacterial strains t that arise from existing therapeutic treatments.
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