Contribution of the novel oxazolidinone TBD09 (MK-7762) to regimens with bedaquiline and pretomanid in a mouse model of tuberculosis
- 1Johns Hopkins University School of Medicine
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 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 estimated the treatment duration to 95% cure for BPa+TBD09 at 2.7 weeks, compared to 3.2 weeks for BPaL, although the time to 50% cure was similar. These results demonstrate that TBD09 provides bactericidal and sterilizing activity similar to linezolid in combination with BPa(M), supporting further clinical development of TBD09 for tuberculosis.
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BibTeX
@misc{almeida2026contribution,
title = {{Contribution of the novel oxazolidinone TBD09 (MK-7762) to regimens with bedaquiline and pretomanid in a mouse model of tuberculosis}},
author = {D. V. Almeida and P. J. Converse and C. Schill and J. I. Lee and M. Levi and A. Berg and M. Khisi and E. L. Nuermberger},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.23.753971},
url = {https://www.biorxiv.org/content/10.64898/2026.09.23.753971v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Contribution of the novel oxazolidinone TBD09 (MK-7762) to regimens with bedaquiline and pretomanid in a mouse model of tuberculosis
AU - D. V. Almeida
AU - P. J. Converse
AU - C. Schill
AU - J. I. Lee
AU - M. Levi
AU - A. Berg
AU - M. Khisi
AU - E. L. Nuermberger
PY - 2026
DA - 2026/09/23
PB - bioRxiv
DO - 10.64898/2026.09.23.753971
UR - https://www.biorxiv.org/content/10.64898/2026.09.23.753971v1
AB - 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 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 estimated the treatment duration to 95% cure for BPa+TBD09 at 2.7 weeks, compared to 3.2 weeks for BPaL, although the time to 50% cure was similar. These results demonstrate that TBD09 provides bactericidal and sterilizing activity similar to linezolid in combination with BPa(M), supporting further clinical development of TBD09 for tuberculosis.
ER -