In vitro and in vivo activities of a novel benzothiopyranone candidate NTB-3119M against Mycobacterium tuberculosis.

Publication date: Jun 02, 2025

NTB-3119M, a novel benzothiopyranone derivative identified through comprehensive drug development studies, was selected as a promising antituberculosis (anti-TB) candidate. This study systematically evaluated its anti-TB efficacy in vitro and in vivo. In vitro analyses encompassed antimicrobial susceptibility testing to determine minimum inhibitory concentrations (MICs) against Mycobacterium tuberculosis H37Rv, 10 drug-susceptible clinical isolates, and 30 multidrug-resistant (MDR) strains, alongside evaluations of minimal bactericidal concentrations (MBCs) using H37Rv and seven clinical isolates. Additionally, intracellular anti-mycobacterial activity was assessed in H37Rv-infected macrophages, and cytotoxicity was profiled through MTT assays on Vero cells. In vivo studies utilized acute and chronic murine tuberculosis infection models to investigate the dose-dependent efficacy of NTB-3119M (50 and 100 mg/kg) against H37Rv, with concurrent comparative histopathological analysis of lung and spleen tissues. NTB-3119M demonstrated superior in vitro potency against both drug-sensitive and drug-resistant M. tuberculosis strains compared to first-line agents, Isoniazid (INH), Rifampicin (RIF), Moxifloxacin (MOFX), Levofloxacin (LVFX), and Streptomycin (SM), exhibiting comparable activity to PBTZ169. Time-kill curves for NTB-3119M indicate its potent bactericidal activity. Meanwhile, No cytotoxicity was observed on Vero cells. Spontaneous resistant mutants of NTB-3119M appears at a frequency of 6. 44 cD7 10 to 3. 65 cD7 10. Most importantly, NTB-3119M demonstrates comparable activity of PBTZ169 and better bactericidal activity against M. tuberculosis than INH and RIF in the 50- and 100- mg/kg groups in acute and chronic murine models. Our research provided comprehensive evidence that NTB-3119M with increased water solubility and bioavailability based on previous research performed excellent anti-tuberculosis activity and less cytotoxicity, which effectively tackled the undesirable drug properties associated with previous benzothiopyrone derivatives. It is warranted that NTB-3119M, as a highly promising candidate anti tuberculosis drug, deserves further research and clinical trial.

Semantics

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