Identification of BMVC-8C3O as a novel Pks13 inhibitor with anti-tuberculosis activity.

IF 2.8 3区医学 Q3 IMMUNOLOGY Tuberculosis Pub Date : 2024-11-19 DOI:10.1016/j.tube.2024.102579

Tianjun Liu, Jianzhou Meng, Bin Wang, Xiaohui Li, Qian Wang, Sihan Liu, Yan Guan, Xiao Wang, Yishuang Liu

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Abstract

Given the increasing prevalence of drug-resistant tuberculosis (TB), there is an urgent demand in developing novel anti-TB medications with highly effective, safe, and utilize innovative mechanisms of action. Blocking the mycolic acid synthesis pathway is well-established to be a significant strategy in developing anti-TB drugs, and Pks13 was identified as a crucial enzyme in this process. Importantly, the modes of action of recognized Pks13 inhibitors differ from traditional anti-TB medications, highlighting Pks13 as a potential and promising target in drug development within TB treatment. In this study, we discovered a compound named BMVC-8C3O that effectively inhibited the activity of Pks13 with a 6.94 μM IC₅₀ value. The binding between BMVC-8C3O and Pks13 was validated through surface plasmon resonance (SPR) assay as well as molecular docking analysis. Moreover, the SPR assay showed that the mutation of Asn1640 and Ser1533 resulted in decreased affinity of BMVC-8C3O to Pks13. Additionally, BMVC-8C3O not only exhibited activity against Mycobacterium tuberculosis (MTB), but also displayed potential intracellular anti-TB activity in macrophages. In summary, our findings indicate that BMVC-8C3O holds great potential as a lead compound against TB.

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鉴定 BMVC-8C3O 为具有抗结核活性的新型 Pks13 抑制剂。

鉴于耐药性结核病（TB）的发病率越来越高，人们迫切需要开发具有高效、安全和利用创新作用机制的新型抗结核药物。阻断霉菌醇酸合成途径已被证实是开发抗结核药物的重要策略，而 Pks13 被认为是这一过程中的关键酶。重要的是，公认的 Pks13 抑制剂的作用模式与传统的抗结核药物不同，这凸显了 Pks13 在结核病治疗药物开发中是一个有潜力和前景的靶点。在这项研究中，我们发现了一种名为 BMVC-8C3O 的化合物，它能有效抑制 Pks13 的活性，IC50 值为 6.94 μM。BMVC-8C3O 与 Pks13 的结合通过表面等离子体共振（SPR）检测和分子对接分析得到了验证。此外，SPR 分析表明，Asn1640 和 Ser1533 的突变导致 BMVC-8C3O 与 Pks13 的亲和力下降。此外，BMVC-8C3O 不仅对结核分枝杆菌（MTB）具有活性，还在巨噬细胞中显示出潜在的细胞内抗结核活性。总之，我们的研究结果表明，BMVC-8C3O 具有作为抗结核先导化合物的巨大潜力。

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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.