Mutations identified in mce3R gene causing contezolid resistance in Mycobacterium tuberculosis

Contezolid is a new oxazolidinone with in vitro and in vivo activity against Mycobacterium tuberculosis comparable to that of linezolid. Pre-clinical and clinical safety studies suggest it may be less toxic than linezolid, making contezolid a potential candidate to replace linezolid in treatment of drug-resistant tuberculosis. We evaluated the dose-ranging activity of contezolid, alone and in combination with bedaquiline and pretomanid, and compared it with linezolid at similar doses, in an established BALB/c mouse model of tuberculosis. Contezolid had an MIC of 1 microgram per ml, similar to linezolid, and exhibited similar bactericidal activity in mice. Contezolid-resistant mutants selected in vitro had 32-to-64-fold increases in contezolid MIC and harbored mutations in the mce3R gene. These mutants did not display cross-resistance to linezolid. Our results indicate that contezolid has potential to replace linezolid in regimens containing bedaquilineand pretomanid and likely other regimens