Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Department of Natural Product Chemistry, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
Int J Mol Sci. 2021 Oct 22;22(21):11432. doi: 10.3390/ijms222111432.
Elicitation through abiotic stress, including chemical elicitors like heavy metals, is a new technique for drug discovery. In this research, the effect of heavy metals on actinobacteria sp. SH-1312 for secondary metabolite production, with strong pharmacological activity, along with pharmacokinetics profile, was firstly investigated. The optimum metal stress conditions consisted of actinobacteria strain sp. SH-1312 with addition of mix metals (Co + Zn) ions at 0.5 mM in Gause's medium. Under these conditions, the stress metabolite anhydromevalonolactone (MVL) was produced, which was absent in the normal culture of strain and other metals combinations. Furthermore, the stress metabolite was also evaluated for its anti-oxidant and cytotoxic activities. The compound exhibited remarkable anti-oxidant activities, recording the IC value of 19.65 ± 5.7 µg/mL in DPPH, IC of 15.49 ± 4.8 against NO free radicals, the IC value of 19.65 ± 5.22 µg/mL against scavenging ability, and IC value of 19.38 ± 7.11 µg/mL for iron chelation capacity and the cytotoxic activities against PC3 cell lines were recorded with IC values of 35.81 ± 4.2 µg/mL after 24 h, 23.29 ± 3.8 µg/mL at 48 h, and 16.25 ± 6.5 µg/mL after 72 h. Further mechanistic studies have revealed that the compound MVL has shown its pharmacological efficacy by upregulation of P53 and BAX while downregulation of BCL-2 expression, indicating that MVL is following apoptosis in varying degrees. To better understand the pharmacological properties of MVL, in this work, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) were also evaluated. During ADMET predictions, MVL has displayed a safer profile in case of hepatotoxicity, cytochrome inhibition and also displayed as non-cardiotoxic. The compound MVL showed good binding energy in the molecular docking studies, and the results revealed that MVL bind in the active region of the target protein of P53 and BAX. This work triumphantly announced a prodigious effect of heavy metals on actinobacteria with fringe benefits as a key tool of MVL production with a strong pharmacological and pharmacokinetic profile.
通过非生物胁迫（包括重金属等化学诱导剂）进行诱导是一种新的药物发现技术。在这项研究中，首次研究了重金属对具有强药理活性的放线菌 sp. SH-1312 产生次生代谢产物的影响，同时还研究了其药代动力学特征。最佳金属胁迫条件为在 Gause 培养基中加入混合金属（Co+Zn）离子 0.5mM 的放线菌 sp. SH-1312 菌株。在这些条件下，产生了应激代谢产物无水甲羟戊酸内酯（MVL），而在正常培养的菌株和其他金属组合中则不存在这种物质。此外，还评估了应激代谢产物的抗氧化和细胞毒性活性。该化合物表现出显著的抗氧化活性，在 DPPH 中记录的 IC 值为 19.65±5.7μg/mL，在 NO 自由基中的 IC 值为 15.49±4.8μg/mL，对清除能力的 IC 值为 19.65±5.22μg/mL，铁螯合能力的 IC 值为 19.38±7.11μg/mL，对 PC3 细胞系的细胞毒性活性在 24 小时后记录的 IC 值为 35.81±4.2μg/mL，在 48 小时后为 23.29±3.8μg/mL，在 72 小时后为 16.25±6.5μg/mL。进一步的机制研究表明，该化合物 MVL 通过上调 P53 和 BAX 同时下调 BCL-2 的表达显示出其药理功效，表明 MVL 正在不同程度地遵循细胞凋亡。为了更好地了解 MVL 的药理特性，在这项工作中，还对其吸收、分布、代谢、排泄和毒性（ADMET）进行了评估。在 ADMET 预测中，MVL 在肝毒性、细胞色素抑制方面表现出更安全的特性，并且也显示出非心脏毒性。化合物 MVL 在分子对接研究中显示出良好的结合能，结果表明 MVL 结合在 P53 和 BAX 靶蛋白的活性区域。这项工作成功地宣布了重金属对放线菌的巨大影响，这是一种具有潜在利益的工具，可以作为具有强大药理和药代动力学特征的 MVL 生产的关键工具。
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