Efficacy of Replacing Linezolid with OTB-658 in Anti-Tuberculosis Regimens in Murine Models.

Abstract

Linezolid (LZD) was the first oxazolidinone approved for treating drug-resistant tuberculosis. A newly approved regimen combining LZD with bedaquiline (BDQ) and pretomanid (PMD) (BPaL regimen) is the first 6-month oral regimen that is effective against multidrug- and extensively drug-resistant tuberculosis. However, LZD toxicity, primarily due to mitochondrial protein synthesis inhibition, may undermine the efficacy of LZD regimens, and oxazolidinones with higher efficacy and lower toxicity during prolonged administration are needed. OTB-658 is an oxazolidinone anti-TB candidate derived from LZD that could replace LZD in TB treatment. We previously found that OTB-658 had better anti-TB activity and safety than LZD in vitro and in vivo. In the present work, two murine TB models were used to evaluate replacing LZD with OTB-658 in LZD-containing regimens. In the C3HeB/FeJ murine model, replacing 100 mg/kg LZD with 50 mg/kg OTB-658 in the BDQ + PMD backbone significantly reduced lung and spleen CFU counts (P < 0.05), and there were few relapses at 8 weeks of treatment. Replacing 100 mg/kg LZD with 50 or 100 mg/kg OTB-658 in the pyrifazimine (previously called TBI-166) + BDQ backbone did not change the anti-TB efficacy and relapse rate. In BALB/c mice, replacing 100 mg/kg LZD with 100 mg/kg OTB-658 in the TBI-166 + BDQ backbone resulted in no culture-positive lungs at 4 and 8 weeks of treatment, and there were no significant differences in relapses rate between the groups. In conclusion, OTB-658 is a promising clinical candidate that could replace LZD in the BPaL or TBI-166 + BDQ + LZD regimens and should be studied further in clinical trials.

• Authors: Haiting Liu, Hui Zhu, Lei Fu, Weiyan Zhang, Xi Chen, Bin Wang, Shaochen Guo, Yangming Ding, Ning Wang, Dongshuo Li, Yu Lu
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 67 Issue 2 Pg. e0139922 (02 16 2023) ISSN: 1098-6596 [Electronic] United States
• PMID: 36622240 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Linezolid
• Antitubercular Agents
• Diarylquinolines
• Oxazolidinones
• pretomanid

Topics

• Animals
• Mice
• Linezolid (therapeutic use, pharmacology)
• Antitubercular Agents (therapeutic use, pharmacology)
• Mycobacterium tuberculosis
• Disease Models, Animal
• Diarylquinolines (therapeutic use, pharmacology)
• Oxazolidinones (therapeutic use)
• Tuberculosis, Multidrug-Resistant (drug therapy)
• Extensively Drug-Resistant Tuberculosis (drug therapy)