Linezolid is an effective oxazolidinone used in the bedaquiline, pretomanid, linezolid (BPaL) regimen for rifampin‑resistant tuberculosis but is limited by dose- and duration-dependent mitochondrial toxicity. TBD09 (formerly MK-7762) is a novel oxazolidinone developed with the goal of retaining antitubercular potency while reducing the adverse-event profile associated with linezolid. The present preclinical work evaluated whether TBD09 can contribute bactericidal and sterilizing activity when combined with bedaquiline and pretomanid (BPa) in a mouse model of tuberculosis.
The investigation used BALB/c mice aerosol-infected with Mycobacterium tuberculosis H37Rv. Treatment was initiated 2 weeks after infection. Two experiments were performed: Experiment 1 assessed dose-ranging bactericidal activity of TBD09 as monotherapy and in combination with BPa, including comparisons with linezolid and sutezolid; Experiment 2 examined sterilizing activity by measuring relapse after various treatment durations when TBD09 was added to BPa or BPa plus moxifloxacin (BPaM).
In Experiment 1, TBD09 was tested at 50, 100, and 200 mg/kg. The compound was evaluated both alone and in combination with bedaquiline and pretomanid (BPa) and compared to linezolid and sutezolid under the same model conditions. Over the initial 4 weeks of treatment, TBD09 given as monotherapy was bacteriostatic, producing an effect similar to that observed with linezolid monotherapy during the same period. Importantly, adding TBD09 to BPa significantly enhanced bactericidal activity relative to BPa alone. The magnitude of enhancement with TBD09 was reported to be comparable to that achieved when linezolid was added to BPa.
Experiment 2 addressed sterilizing activity by assessing relapse after treatment durations ranging from 4 to 22 weeks. TBD09 at 200 mg/kg was evaluated in combination with BPa and with BPa plus moxifloxacin (BPaM). Relapse outcomes showed that BPa+TBD09 resulted in significantly fewer relapses than BPa alone after 14 weeks of treatment. Similarly, BPaM+TBD09 produced significantly fewer relapses compared to BPaM after 10 weeks of treatment. These relapse assessments indicate that TBD09 improves the regimen's ability to prevent recurrence following treatment in this murine model.
A model-based analysis was performed to estimate durations required to achieve high probabilities of cure. The model estimated the time to 95% cure at 2.7 weeks for BPa+TBD09 versus 3.2 weeks for BPa+linezolid. The time to 50% cure was reported as similar between the regimens. These modeled estimates suggest a modest advantage for TBD09 in the duration needed to achieve a high probability of cure when combined with BPa.
Taken together, these results in a murine tuberculosis model indicate that TBD09 provides bactericidal and sterilizing activity comparable to linezolid when combined with bedaquiline and pretomanid, supporting its advancement into further clinical development for tuberculosis.
This report is a preprint and the data have not been peer reviewed. Details beyond the summary provided in the abstract—such as full methods, statistical analyses, safety or toxicity data in mice, pharmacokinetics, and any comparative adverse‑event profiling—were not reported in the abstract and therefore are not summarized here. Further work reported in peer-reviewed publications or clinical studies will be required to confirm safety, tolerability, and efficacy in humans and to define optimal dosing and duration.
In a BALB/c mouse model of M. tuberculosis infection, TBD09 (MK-7762) augmented the bactericidal and sterilizing effects of regimens containing bedaquiline and pretomanid, performing similarly to linezolid in these preclinical assessments and warranting further development. The findings are preliminary pending peer review and additional data.