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Targeted genome mining for microbial antitumor agents acting through DNA intercalation.

ABSTRACT: Microbial natural products have been one of the most important sources for drug development. In the current postgenomic era, sequence-driven approaches for natural product discovery are becoming increasingly popular. Here, we develop an effective genome mining strategy for the targeted discovery of microbial metabolites with antitumor activities. Our method employs uvrA-like genes as genetic markers, which have been identified in the biosynthetic gene clusters (BGCs) of several chemotherapeutic drugs of microbial origin and confer self-resistance to the corresponding producers. Through systematic genomic analysis of gifted actinobacteria genera, identification of uvrA-like gene-containing BGCs, and targeted isolation of products from a BGC prioritized for metabolic analysis, we identified a new tetracycline-type DNA intercalator timmycins. Our results thus provide a new genome mining strategy for the efficient discovery of antitumor agents acting through DNA intercalation.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC10413001 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Targeted genome mining for microbial antitumor agents acting through DNA intercalation.

Zhao Zhijie Z Zhao Guiyun G Chai Yi Y Li Wei W Song Kaihui K Zhao Wenbin W Li Hairong H Wu Miaolian M Zhou Zhan Z Du Yi-Ling YL

Synthetic and systems biotechnology 20230722 3

Microbial natural products have been one of the most important sources for drug development. In the current postgenomic era, sequence-driven approaches for natural product discovery are becoming increasingly popular. Here, we develop an effective genome mining strategy for the targeted discovery of microbial metabolites with antitumor activities. Our method employs <i>uvrA</i>-like genes as genetic markers, which have been identified in the biosynthetic gene clusters (BGCs) of several chemothera ...[more]

PMID: 37575356

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Project description:Background:Breast cancer is the leading cause of cancer death in women. Chemotherapy to inhibit the proliferation of cancer cells is considered to be the most important therapeutic strategy. The development of long-circulating PEG and targeting liposomes is a major advance in drug delivery. However, the techniques used in liposome preparation mainly involve conventional liposomes, which have a short half-life, high concentrations in the liver and spleen reticuloendothelial system, and no active targeting. Methods:Four kinds of paclitaxel liposomes were prepared and characterized by various analytical techniques. The long-term targeting effect of liposomes was verified by fluorescence detection methods in vivo and in vitro. Pharmacokinetic and acute toxicity tests were conducted in ICR mice to evaluate the safety of different paclitaxel preparations. The antitumor activity of ES-SSL-PTX was investigated in detail using in vitro and in vivo human breast cancer MCF-7 cell models. Results:ER-targeting liposomes had a particle size of 137.93±1.22 nm and an acceptable encapsulation efficiency of 88.07±1.25%. The liposome preparation is best stored at 4°C, and is stable for up to 48 hrs. Cytotoxicity test on MCF-7 cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. We used the near-infrared fluorescence imaging technique to confirm that ES-SSL-PTX was effectively targeted and could quickly and specifically identify the tumor site. Pharmacokinetics and acute toxicity in vivo experiments were carried out. The results showed that ES-SSL-PTX could significantly prolong the half-life of the drug, increase its circulation time in vivo, improve its bioavailability and reduce its toxicity and side effects. ES-SSL-PTX can significantly improve the pharmacokinetic properties of paclitaxel, avoid allergic reaction of the original solvent, increase antitumor efficacy and reduce drug toxicity and side effects. Conclusion:ES-SSL-PTX has great potential for improving the treatment of breast cancer, thereby improving patient prognosis and quality of life.

Dataset Information

Targeted genome mining for microbial antitumor agents acting through DNA intercalation.

Publications

Targeted genome mining for microbial antitumor agents acting through DNA intercalation.

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