Exploring the anti-tuberculosis activity mechanism of OTB-658: Multi-omics analysis

OTB-658, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid (LZD) in combination with bedaquiline and pretomanid (BPaL). Preclinical evaluations have demonstrated its superior efficacy profile compared to LZD, coupled with enhanced safety characteristics in cellular models and animal studies, positioning it as a potential successor to address current therapeutic limitations. However, the mechanisms underlying these actions have not been completely elucidated. In this study, multi-omics analyses are employed to detect regularities and patterns that reveal the action mechanism of OTB-658. The clinically drug-resistant strains showed significant cross-resistance to both LZD and OTB-658, and identical mutation sites to those of LZD were also identified, indicating that these inhibitors might exert their effects through an overlapping mechanism. Through an integrative approach combining whole genome, proteomics, transcriptomics, the results suggest that OTB-658 exerts its antimicrobial effects by targeting the 50S ribosomal subunit, thereby disrupting bacterial protein synthesis. This study is significant for advancing the drug's clinical trial research process and the application of OTB-658 in the treatment.