Binding-induced thermal stabilization of mosR and ndhA G-quadruplex comprising genes by emodin leads to downregulation and growth inhibition in Mtb: Potential as anti-tuberculosis drug

Abstract

Non-canonical G-quadruplex (G4) DNAs in genome of living organisms are involved inregulation of several cellular activities. Understanding of G-quadruplex interaction with anthraquinones is significant, in the continuing search for an effective therapeutic target against tuberculosis disease causing Mycobacterium tuberculosis virulent strains. Emodin interacts with G4 DNA forming genes, mosR and ndhA, that are essential in ATP synthesis and hypoxic growth of bacterial strains inside host cell. The observed hypochromism, red shift ∼ 6–11 nm, fluorescence quenching, shortening of fluorescence lifetime and appearance of negative induced circular dichroism band during interaction suggest binding of emodin to grooves/loops and end stacking with guanine quartets. The thermodynamically favorable reaction, involving non-intercalative binding mechanism in two distinct modes, is enthalpy driven with affinity constant ∼ 6 × 104 M−1. Inhibition of bacterial growth, Taq polymerase enzyme and significant downregulation of mosR and ndhA genes (2–4 orders) by emodin may be attributed to binding-induced thermal stabilization, ΔTm ∼ 23 and 14 °C in ndhA and mosR G4 DNA complexes, respectively. The studies demonstrate G4 DNA as promising pharmacological targets for developing effective anti-tuberculosis treatments and therapeutic potential of emodin in targeting pathogen persistence genes, particularly in view of emerging multi drug resistant deadly strains.