Cyclic Amide-Linked Oxazolidinone Triazoles as Inhibitors of the T-Box Riboswitch

Area of Science:

• Microbiology
• Drug Discovery
• RNA Biology

Background:

• Antimicrobial resistance (AMR) is a critical global health threat, exacerbated by the COVID-19 pandemic.
• Novel antibacterial strategies targeting unconventional mechanisms are urgently needed.
• Bacterial riboswitches, particularly the T-box riboswitch found in Gram-positive bacteria, regulate essential gene expression and represent an attractive therapeutic target.

Purpose of the Study:

• To explore oxazolidinone- and triazole-based compounds as potential inhibitors of the T-box riboswitch.
• To design and synthesize novel macrocyclic oxazolidinone scaffolds with enhanced RNA-binding affinity and stereoselectivity.
• To investigate the mechanism of inhibition of T-box riboswitch activity by designed compounds.

Main Methods:

• Design and synthesis of macrocyclic oxazolidinone compounds.
• In vitro assays to assess inhibition of T-box riboswitch transcriptional readthrough.
• Computational docking studies to predict binding interactions with the T-box riboswitch antiterminator region.

Main Results:

• A synthetically viable macrocyclic oxazolidinone candidate was identified.
• Computational docking suggested potential interference with tRNA-induced transcription via π-π stacking interactions with G5.
• Prior tricyclic oxazolidinones showed in vitro inhibition but limited disruption of the tRNA-antiterminator complex.

Conclusions:

• Structurally optimized small molecules targeting the T-box riboswitch show potential as a novel antibacterial strategy.
• Macrocyclic oxazolidinones represent a promising scaffold for developing T-box riboswitch inhibitors.
• Further investigation is warranted to validate these compounds as effective antibacterial agents.