Contribution of the novel oxazolidinone TBD09 (MK-7762) to regimens with bedaquiline and pretomanid in a mouse model of tuberculosis
Abstract
ABSTRACT: Linezolid is a key component of the bedaquiline, pretomanid, linezolid (BPaL) regimen for rifampin-resistant tuberculosis, but dose-and duration-dependent mitochondrial toxicity frequently limits its use. TBD09 (formerly MK-7762) is a novel oxazolidinone developed to maintain antitubercular potency comparable to linezolid while reducing mitochondrial protein synthesis inhibition and related adverse events. We evaluated the contribution of TBD09 to the bactericidal and sterilizing activities of BPa-based regimens in a murine tuberculosis model. BALB/c mice were aerosol-infected with Mycobacterium tuberculosis H37Rv and treated starting 2 weeks post-infection. In Experiment 1, dose-ranging bactericidal activity of TBD09 (50, 100, 200 mg/kg) was assessed alone and in combination with BPa, with comparison to linezolid and sutezolid. In Experiment 2, the sterilizing activity of TBD09 (200 mg/kg) in combination with BPa and BPa plus moxifloxacin (M) was assessed by evaluating relapse after treatment durations of 4-22 weeks. TBD09 monotherapy was bacteriostatic, similar to linezolid over the first 4 weeks of treatment. The addition of TBD09 to BPa significantly enhanced bactericidal activity comparable to the addition of linezolid. In relapse assessments, BPa+TBD09 resulted in significantly fewer relapses compared to BPa alone after 14 weeks of treatment, and BPaM+TBD09 resulted in significantly fewer relapses compared to BPaM after 10 weeks. Model-based analysis…
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