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

IF 2.9 3区医学 Q3 IMMUNOLOGY

Tuberculosis Pub Date : 2025-06-02 DOI:10.1016/j.tube.2025.102654

Manyi Xu , Lei Zhang , Bin Wang , Lei Fu , Shaochen Guo , Xi Chen , Weiyan Zhang , Gang Li , Peng Li , Haihong Huang , Yu Lu

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Abstract

Objectives

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.

Methods

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.

Results

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 × 10⁻⁷ to 3.65 × 10⁻⁶. 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.

Conclusion

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.

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新型苯并噻吩吡喃酮候选物NTB-3119M抗结核分枝杆菌的体内外活性研究

目的通过综合药物开发研究，鉴定出一种新型苯并噻吩吡喃酮衍生物ntb - 3119m，作为抗结核药物的候选药物。本研究系统评价了其体外和体内抗结核效果。方法采用体外药敏试验确定对结核分枝杆菌H37Rv、10株药敏临床分离株和30株多药耐药（MDR）菌株的最低抑菌浓度（mic），同时对H37Rv和7株临床分离株的最低杀菌浓度（MBCs）进行评估。此外，在h37rv感染的巨噬细胞中评估细胞内抗分枝杆菌活性，并通过MTT测定Vero细胞的细胞毒性。体内研究采用急性和慢性小鼠结核感染模型，研究NTB-3119M（50和100 mg/kg）对H37Rv的剂量依赖性作用，同时对肺和脾组织进行比较组织病理学分析。结果与一线药物异烟肼（INH）、利福平（RIF）、莫西沙星（MOFX）、左氧氟沙星（LVFX）和链霉素（SM）相比，sntb - 3119m对药敏和耐药结核分枝杆菌均表现出更强的体外药效，其活性与PBTZ169相当。NTB-3119M的时间杀伤曲线表明其具有较强的杀菌活性。同时，对Vero细胞无细胞毒性作用。NTB-3119M的自发耐药突变体出现频率为6.44 × 10−7 ~ 3.65 × 10−6。最重要的是，在急性和慢性小鼠模型中，NTB-3119M在50和100 mg/kg组中表现出与PBTZ169相当的活性，并且对结核分枝杆菌的杀菌活性优于INH和RIF。结论NTB-3119M具有较高的水溶性和生物利用度，具有较好的抗结核活性和较低的细胞毒性，有效地解决了以往苯并噻唑吡酮类药物的不良药性问题。NTB-3119M作为一种极具发展前景的抗结核候选药物，值得进一步研究和临床试验。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tuberculosis 医学-呼吸系统

CiteScore

4.60

自引率

3.10%

发文量

审稿时长

49 days

期刊介绍： Tuberculosis is a speciality journal focusing on basic experimental research on tuberculosis, notably on bacteriological, immunological and pathogenesis aspects of the disease. The journal publishes original research and reviews on the host response and immunology of tuberculosis and the molecular biology, genetics and physiology of the organism, however discourages submissions with a meta-analytical focus (for example, articles based on searches of published articles in public electronic databases, especially where there is lack of evidence of the personal involvement of authors in the generation of such material). We do not publish Clinical Case-Studies. Areas on which submissions are welcomed include: -Clinical TrialsDiagnostics- Antimicrobial resistance- Immunology- Leprosy- Microbiology, including microbial physiology- Molecular epidemiology- Non-tuberculous Mycobacteria- Pathogenesis- Pathology- Vaccine development. This Journal does not accept case-reports. The resurgence of interest in tuberculosis has accelerated the pace of relevant research and Tuberculosis has grown with it, as the only journal dedicated to experimental biomedical research in tuberculosis.