Characterization of G-Quadruplex Motifs in espB, espK, and cyp51 Genes of Mycobacterium tuberculosis as Potential Drug Targets

Mishra, Subodh Kumar; Shankar, Uma; Jain, Neha; Sikri, Kriti; Tyagi, Jaya Sivaswami; Sharma, Tarun Kumar; Mergny, Jean-Louis; Kumar, Amit

Recently, G4s were recognized as highly conserved and promising drug targets for combating the infection of various polymorphic and lethal human pathogens. 11, 47 For example, the presence of the G4 motif in the pre-S2/S gene promoter upregulates the activity of HBV inside human cells. 48 Recently, G4 motifs in the genes of the various structural proteins of the Zika virus were found to be promising drug targets. 49 Similarly, in the case of the Kaposi's sarcoma-associated herpesvirus (KSHV), a G4 motif was found to lie in between the kaposin (DR6) and oriLyt-R, oriLyt-L and K5 9, and v-IRF2 and v-IRF3 genes, and was observed to regulate the replication and transcription of the viral genome inside the host cell. 50 In HIV, a G4 found at unique long terminal repeat (LTR) promoter regions has been proposed as a potent target for anti-HIV therapy. 51 The pac1 signal required for successful cleavage and packaging of the Human Herpesvirus, and the presence of the G4 motif in this region suggested their novel function in the viral genome. 52 Altogether, bioinformatics analysis, 1D 1 H NMR, CD spectroscopy, and EMSA revealed the presence of 100% conserved intramolecular parallel G4-forming motifs in three essential bacterial genes, namely, espK (Rv3879c), espB (Rv3881c), and cyp51 (Rv0764c). Similar to the G4 target in the above-mentioned human pathogen, a G4 motif present in these genes may also serve as a potential target for developing an anti-bacterial therapy. These G-rich targets can also overcome the problem of the drug resistance because of their 100% conservation in both drug-susceptible and drug-resistant bacterial strains (including extremely drug-resistant strains).