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荭草素通过靶向 ClpP 降低 MRSA 诱导肺炎感染的毒力因子表达。

Nepetin reduces virulence factors expression by targeting ClpP against MRSA-induced pneumonia infection.

机构信息

Clinical Medical College, Changchun University of Chinese Medicine, Changchun, China.

School of Pharmaceutical Science, Jilin University, Changchun, China.

出版信息

Virulence. 2022 Dec;13(1):578-588. doi: 10.1080/21505594.2022.2051313.

DOI:10.1080/21505594.2022.2051313
PMID:35363605
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8986306/
Abstract

The resistance of () to various antibiotics has increased dramatically due to the misuse of antibiotics, and thus the development of new anti-infective drugs with new targets is urgently needed to combat resistance. Caseinolytic peptidase P is a case in hydrolase that regulates the virulence level of . Here, we found that nepetin, a small-molecule compound from traditional Chinese herbal flavonoids, effectively inhibits ClpP activity. Nepetin suppressed the virulence of and effectively combated the lethal pneumonia caused by MRSA. The results of cellular thermal shift assay showed that nepetin could bind to ClpP and reduce the thermal stability of ClpP, and the value of 602 nM between them was determined using localized surface plasmon resonance. The binding mode of nepetin and ClpP was further investigated by molecular docking, and it was found that Ser-22 and Gln-47 of ClpP residues were found to be involved in the binding of nepetin to ClpP. In conclusion, we determined that nepetin is a ClpP inhibitor and an effective lead compound for the development of a virulence factor-based treatment for MRSA infection.

摘要

由于抗生素的滥用，()对各种抗生素的耐药性急剧增加，因此迫切需要开发具有新靶点的新型抗感染药物来对抗耐药性。天冬氨酸蛋白酶 P 是一种调节 毒力水平的水解酶。在这里，我们发现从传统中药类黄酮中提取的小分子化合物橙皮素能有效抑制 ClpP 活性。橙皮素抑制了 的毒力，并有效对抗了 MRSA 引起的致命性肺炎。细胞热转移试验的结果表明，橙皮素能够与 ClpP 结合并降低 ClpP 的热稳定性，并用局部表面等离子体共振法确定了它们之间 602nm 的 值。通过分子对接进一步研究了橙皮素与 ClpP 的结合模式，发现 ClpP 残基中的 Ser-22 和 Gln-47 参与了橙皮素与 ClpP 的结合。总之，我们确定橙皮素是一种 ClpP 抑制剂，也是一种基于毒力因子的治疗 MRSA 感染的有效先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/dc225b9104a3/KVIR_A_2051313_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/78aeb5c1b7e5/KVIR_A_2051313_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/3d9ebc9ed333/KVIR_A_2051313_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/3c94d4e1c7a9/KVIR_A_2051313_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/dc225b9104a3/KVIR_A_2051313_F0004_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/78aeb5c1b7e5/KVIR_A_2051313_F0001_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/3d9ebc9ed333/KVIR_A_2051313_F0002_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/3c94d4e1c7a9/KVIR_A_2051313_F0003_OC.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d5b0/8986306/dc225b9104a3/KVIR_A_2051313_F0004_OC.jpg

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