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

## TL;DR

This paper explores new antibiotic compounds that target a specific RNA structure in bacteria, offering a novel approach to combat antimicrobial resistance.

## Contribution

The study introduces a macrocyclic oxazolidinone scaffold designed to improve RNA-binding affinity and inhibit T-box riboswitch function.

## Key findings

- A macrocyclic oxazolidinone compound was identified that may interfere with tRNA-induced transcription through π–π stacking interactions.
- Computational docking suggests the compound interacts with the antiterminator region of the T-box riboswitch.
- The T-box riboswitch is a promising target for antibacterial agents due to its conserved nature and regulatory role in essential genes.

## Abstract

Antimicrobial resistance remains a critical global health challenge, and was intensified by the COVID-19 pandemic. To address this growing threat, novel antibacterial agents targeting unconventional mechanisms are urgently needed. One promising strategy involves inhibiting bacterial riboswitches—RNA elements that regulate gene expression. Unlike most riboswitches that respond to small-molecule metabolites, the T-box riboswitch uniquely binds non-aminoacylated tRNA and is predominantly found in Gram-positive bacteria, making it an attractive target due to its conserved sequences and regulatory role over essential genes. This study explored oxazolidinone- and triazole-based compounds as potential inhibitors of the T-box riboswitch. Prior investigations into tricyclic oxazolidinones revealed an allosteric modulator that effectively inhibited T-box riboswitch transcriptional readthrough in vitro, though it showed limited disruption of the isolated tRNA–antiterminator complex. To enhance RNA-binding affinity and stereoselectivity, a macrocyclic oxazolidinone scaffold was designed, incorporating a strategic substituent to expand the interaction footprint. A synthetically viable candidate was identified, and computational docking studies suggested that one of the designed compounds may interfere with tRNA-induced transcription by forming π–π stacking interactions with G5 in the antiterminator region. These findings support the potential of targeting the T-box riboswitch with structurally optimized small molecules as a novel antibacterial strategy.