Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine and Linezolid in a Murine Model of Tuberculosis.

Wei, Y.; Yusuf, B.; Shuai, W.; Xirong, T.; Hameed, H. M. A.; Zhili, L.; Chiwala, G.; Alam, M. S.; Cook, G. M.; Maslov, D. A.; Nanshan, Z.; Zhang, T.

doi:10.1101/2021.04.04.438375

bioRxiv · 10.1101/2021.04.04.438375

Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine and Linezolid in a Murine Model of Tuberculosis.

Wei, Y.·Yusuf, B.·Shuai, W.·Xirong, T.·Hameed, H. M. A.·Zhili, L.·Chiwala, G.·Alam, M. S.·Cook, G. M.·Maslov, D. A.·Nanshan, Z.·Zhang, T.

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Abstract

Toxicity and inconvenience associated with the use of injectable drug-containing regimens for tuberculosis (TB) have made all-oral regimens a preferred alternative. Widespread resistance to fluoroquinolones and pyrazinamide makes it essential to identify new drug candidates and study their effects on current regimens for TB. TB47 is a pyrazolo[1,5-a]pyridine-3-carboxamide with powerful synergistic in vitro and in vivo activities against mycobacteria, especially with clofazimine. Here, we investigated the bactericidal and sterilizing activities of novel oral regimens containing TB47 + clofazimine + linezolid, and the potential roles of levofloxacin and/or pyrazinamide in such drug combinations. Using a well-established mouse model, we assessed the effect of these regimens on bacterial burden in the lung during treatment and relapse (4 months after stopping treatment + immunosuppression). Our findings indicate that the TB47 + clofazimine + linezolid + pyrazinamide, with/without levofloxacin, regimens had fast-acting (4 months) sterilizing activity and no relapse was observed. When pyrazinamide was excluded from the regimen, treatment times were longer (5-6 months) to achieve sterilizing conditions. We propose that TB47 + clofazimine + linezolid can form a highly sterilizing block for use as an alternative pan-TB regimen.

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Wei, Y., Yusuf, B., Shuai, W., Xirong, T., Hameed, H. M. A., Zhili, L., Chiwala, G., Alam, M. S., Cook, G. M., Maslov, D. A., Nanshan, Z., Zhang, T.. 2021-04-04. Sterilizing Effects of Novel Regimens Containing TB47, Clofazimine and Linezolid in a Murine Model of Tuberculosis.. https://doi.org/10.1101/2021.04.04.438375

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