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

Abstract

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.

• Authors: Shaochen Guo, Lei Fu, Bin Wang, Xi Chen, Jiaojie Zhao, Mingliang Liu, Yu Lu
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 131 Pg. 110777 (Nov 2020) ISSN: 1950-6007 [Electronic] France
• PMID: 33152936 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Antitubercular Agents
• Piperazines
• Thiazines
• Piperazine
• macozinone

Topics

• Animals
• Antitubercular Agents (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Female
• Macrophages (drug effects, microbiology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C3H
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects, isolation & purification)
• Piperazine (chemistry)
• Piperazines (administration & dosage, chemistry, pharmacology)
• Thiazines (administration & dosage, chemistry, pharmacology)
• Time Factors
• Tuberculosis (drug therapy, microbiology)
• Tuberculosis, Multidrug-Resistant (drug therapy, microbiology)