In vitro and in vivo antimicrobial activities of a novel piperazine-containing benzothiazinones candidate TZY-5-84 against Mycobacterium tuberculosis - 28/10/20
, Yu Lu a, ⁎ Bienvenue sur EM-consulte, la référence des professionnels de santé.
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Highlights |
• | TZY-5-84 is one of PBTZ169 analogues with anti-tuberculosis activity both in vitro and in vivo. |
• | TZY-5-84 has preferable AUC0→∞, Cmax and bioavailability (F(%)). |
• | No antagonism was observed between TZY-5-84 and commonly used anti-tuberculosis drugs. |
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.
Le texte complet de cet article est disponible en PDF.Abbreviations : BDQ, BTZs, CFU, CFZ, DEL, DprE1, FADH2, FICI, INH, LFX, LZD, MBC, MDR, MIC, MTB, PA-824, PZA, RFP, RR, SAR, SM, TB, WHO, XDR
Keywords : piperazine-containing benzothiazinone analogue, DprE1 inhibitor, Mycobacterium tuberculosis, anti-tuberculosis activity
Plan
Vol 131
Article 110777- novembre 2020 Retour au numéro
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