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脂肪酸和威斯塔汀对菌株抗毒力作用的变化。

Variations in the Antivirulence Effects of Fatty Acids and Virstatin against Strains.

机构信息

Department of Pharmacy, College of Pharmacy, Hanyang University, Ansan 15588, Republic of Korea.

Institute of Pharmacological Research, Hanyang University, Ansan 15588, Republic of Korea.

出版信息

J Microbiol Biotechnol. 2024 Sep 28;34(9):1757-1768. doi: 10.4014/jmb.2405.05002. Epub 2024 Jul 19.

DOI:10.4014/jmb.2405.05002
PMID:39187456
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11485679/
Abstract

The expression of two major virulence factors of , cholera toxin (CT) and toxin co-regulated pilus (TCP), is induced by environmental stimuli through a cascade of interactions among regulatory proteins known as the ToxR regulon when the bacteria reach the human small intestine. ToxT is produced via the ToxR regulon and acts as the direct transcriptional activator of CT (), TCP ( gene cluster), and other virulence genes. Unsaturated fatty acids (UFAs) and several small-molecule inhibitors of ToxT have been developed as antivirulence agents against . This study reports the inhibitory effects of fatty acids and virstatin (a small-molecule inhibitor of ToxT) on the transcriptional activation functions of ToxT in isogenic derivatives of strains containing various alleles. The fatty acids and virstatin had discrete effects depending on the ToxT allele (different by 2 amino acids), strain, and culture conditions, indicating that strains could overcome the effects of UFAs and small-molecule inhibitors by acquiring point mutations in . Our results suggest that small-molecule inhibitors should be examined thoroughly against various strains and alleles during development.

摘要

当细菌到达人体小肠时，通过一系列称为 ToxR 调控子的调节蛋白之间的相互作用，两种主要毒力因子霍乱毒素 (CT) 和毒素调节菌毛 (TCP) 的表达被环境刺激诱导。ToxT 通过 ToxR 调控子产生，作为 CT ()、TCP (基因簇) 和其他毒力基因的直接转录激活因子。不饱和脂肪酸 (UFAs) 和几种 ToxT 的小分子抑制剂已被开发为针对 的抗病毒药物。本研究报告了脂肪酸和维司他汀（一种 ToxT 的小分子抑制剂）对含有不同 等位基因的 菌株同源衍生菌株中 ToxT 转录激活功能的抑制作用。脂肪酸和维司他汀的作用因 ToxT 等位基因（相差 2 个氨基酸）、菌株和培养条件而异，这表明 菌株可以通过在 中获得点突变来克服 UFAs 和小分子抑制剂的作用。我们的研究结果表明，在开发过程中，小分子抑制剂应针对各种 菌株和 等位基因进行彻底检查。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/5b9fca489f1c/jmb-34-9-1757-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/182f8877e9ac/jmb-34-9-1757-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/3e31023d0630/jmb-34-9-1757-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/19a87e0373dd/jmb-34-9-1757-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/86cfc3dfbfc9/jmb-34-9-1757-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/8481930f9d61/jmb-34-9-1757-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/5b9fca489f1c/jmb-34-9-1757-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/182f8877e9ac/jmb-34-9-1757-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/3e31023d0630/jmb-34-9-1757-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/19a87e0373dd/jmb-34-9-1757-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/86cfc3dfbfc9/jmb-34-9-1757-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/8481930f9d61/jmb-34-9-1757-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c4c/11485679/5b9fca489f1c/jmb-34-9-1757-f6.jpg

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本文引用的文献

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Toxins (Basel). 2023 Aug 17;15(8):507. doi: 10.3390/toxins15080507.
2
Intracellular Expression of CTB in Strains in Laboratory Culture Conditions.实验室培养条件下 CTB 在菌株中的细胞内表达。
J Microbiol Biotechnol. 2023 Jun 28;33(6):736-744. doi: 10.4014/jmb.2302.02014. Epub 2023 Apr 6.
3
Development of a smart pH-responsive nano-polymer drug, 2-methoxy-4-vinylphenol conjugate against the intestinal pathogen, Vibrio cholerae.
一种智能 pH 响应纳米聚合物药物的研制，2-甲氧基-4-乙烯基苯酚偶联物针对肠道病原体霍乱弧菌。
Sci Rep. 2023 Jan 23;13(1):1250. doi: 10.1038/s41598-023-28033-0.
4
Inactivated Strains That Express TcpA via the -139F Allele Induce Antibody Responses against TcpA.通过 -139F 等位基因表达 TcpA 的失活菌株诱导针对 TcpA 的抗体应答。
J Microbiol Biotechnol. 2022 Nov 28;32(11):1396-1405. doi: 10.4014/jmb.2209.09001. Epub 2022 Oct 12.
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Emerging Concepts in Cholera Vaccine Design.霍乱疫苗设计的新观念。
Annu Rev Microbiol. 2022 Sep 8;76:681-702. doi: 10.1146/annurev-micro-041320-033201. Epub 2022 Jun 27.
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Elucidating the correlation between the number of TTTTGAT heptamer repeats and cholera toxin promoter activity in Vibrio cholerae O1 pandemic strains.阐明霍乱弧菌O1大流行菌株中TTTTGAT七聚体重复序列数量与霍乱毒素启动子活性之间的相关性。
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