In vitro and in vivo antimicrobial activities of a novel piperazine-containing benzothiazinones candidate TZY-5-84 against Mycobacterium tuberculosis

Guo, S.; Fu, L.; Wang, B.; Chen, X.; Zhao, J.; Liu, M.; Lu, Y.

Biomedicine and PharmacoTherapy 131: 110777


ISSN/ISBN: 0753-3322
PMID: 33152936
DOI: 10.1016/j.biopha.2020.110777
Accession: 071951225

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A piperazine-containing benzothiazinones lead compound PBTZ169, served as DprE1 inhibitor, displays nanomolar bactericidal activity against Mycobacteria tuberculosis. Here, we systematically evaluate anti-tuberculosis activity of one of PBTZ169 analogues, TZY-5-84, in vitro and in vivo. The MIC value of TZY-5-84 against M. tuberculosis H37Rv ranged from 0.014 to 0.015 mg/L, lower than those of INH, RFP and BDQ. Five susceptible and thirteen drug-resistant clinical isolates were also susceptive to TZY-5-84. It had anti-tuberculosis activity against intracellular bacilli in infected macrophage model. It exhibited its activity in time-dependent manner and against intracellular bacilli in infected macrophage cells. However, the MIC of TZY-5-84 against three laboratory PBTZ169-induced resistant isolates increased four-fold increment compared to that of H37Rv. No antagonism was observed in any combination between TZY-5-84 and seven commonly used anti-tuberculosis drugs in an in vitro checkerboard assay. In murine infection model, TZY-5-84 at lower dosage (12.5 mg/kg) was found to be comparatively efficacious as PBTZ169 at 25 mg/kg. Our research suggests TZY-5-84 can be a promising preclinical candidate for further study on TB treatment.