Abstract
G-quadruplexes (G4s) are non-canonical DNA structures that could be considered as potential therapeutic targets for antimicrobial compounds, also known as G4-stabilizing ligands. While some of these ligands are shown in vitro to have a stabilizing effect, the precise mechanism of antibacterial action has not been fully investigated. Here, we employed genome-wide RNA-sequencing to analyze the response of Mycobacterium smegmatis to inhibitory concentrations of BRACO-19 and TMPyP4 G4 ligands. The expression profile changed (FDR < 0.05, log2FC > |1|) for 822 (515↑; 307↓) genes in M. smegmatis in response to BRACO-19 and for 680 (339↑; 341↓) genes in response to TMPyP4. However, the analysis revealed no significant ligand-induced changes in the expression levels of G4-harboring genes, genes under G4-harboring promoters, or intergenic regions located on mRNA-like or template strands. Meanwhile, for the BRACO-19 ligand, we found significant changes in the replication and repair system genes, as well as in iron metabolism genes which is, undoubtedly, evidence of the induced stress. For the TMPyP4 compound, substantial changes were found in transcription factors and the arginine biosynthesis system, which may indicate multiple biological targets for this compound.
Highlights
The emergence and rapid dissemination of drug-resistant bacterial pathogens are becoming a global health challenge
To understand how G4-stabilizing compounds affect gene expression levels, the transcriptomic profiles of M. smegmatis MC2155 strain exposed to BRACO-19 and TMPyP4 for 4 h
According to dilution-based antimicrobial susceptibility testing, BRACO-19 and TMPyP4 had in vitro minimum inhibitory concentration (MIC) values of 10 and 4 μM, respectively (Supplementary Figure S1)
Summary
The emergence and rapid dissemination of drug-resistant bacterial pathogens are becoming a global health challenge. In 2019, an estimated 10 million people worldwide developed tuberculosis (TB), caused by Mycobacterium tuberculosis complex bacteria. Nearly half a million people have developed rifampicin-resistant TB (RR-TB), 78% of whom had multidrug-resistant TB (MDR-TB; resistance to both first-line drugs rifampin and isoniazid). The global treatment success rate for MDR/RR-TB was estimated at 57%, compared to an overall success rate of 85% for all cases. The treatment of people with resistant TB forms takes longer and requires more expensive and toxic drugs (Seung et al, 2015; Global Tuberculosis Report 2020, 2020). All of these factors encourage the development of new anti-TB agents with new mechanisms of action
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