Clinical Medical College, Changchun University of Chinese Medicinegrid.440665.5, Changchun, China.
School of Traditional Chinese Medicine, Changchun University of Chinese Medicinegrid.440665.5, Changchun, China.
Microbiol Spectr. 2022 Apr 27;10(2):e0234021. doi: 10.1128/spectrum.02340-21. Epub 2022 Mar 23.
The dramatic increase of methicillin-resistant Staphylococcus aureus (MRSA) poses a great challenge to the treatment of Staphylococcus aureus (S. aureus) infections. Therefore, there is an urgent need to identify novel anti-infective agents to attack new targets to overcome antibiotic resistance. Casein hydrolase P (ClpP) is a key virulence factor in S. aureus to maintain cellular homeostasis. We screened from flavonoids and finally determined that quercetin could effectively attenuate the virulence of MRSA. The results of the thermal shift assay showed that quercetin could bind to ClpP and reduce the thermal stability of ClpP, and the value between quercetin and ClpP was 197 nM as determined by localized surface plasmon resonance. We found that quercetin exhibited a protective role of a mouse model of MRSA-induced lethal infection in a murine model. Based on the above facts, quercetin, as a ClpP inhibitor, could be further developed as a potential candidate for antivirulence agents to combat S. aureus infections. The resistance of Staphylococcus aureus (S. aureus) to various antibiotics has increased dramatically, and thus the development of new anti-infective drugs with new targets is urgently needed to combat resistance. Caseinolytic peptidase P (ClpP) is a casein hydrolase that has been shown to regulate a variety of important virulence factors in S. aureus. Here, we found that quercetin, a small-molecule compound from traditional Chinese herbal flavonoids, effectively inhibits ClpP activity. Quercetin attenuates the expression of multiple virulence factors in S. aureus and effectively protects mice from lethal pneumonia caused by MRSA. In conclusion, we determined that quercetin is a ClpP inhibitor and an effective lead compound for the development of a virulence factor-based treatment for S. aureus infection.
耐甲氧西林金黄色葡萄球菌 (MRSA) 的急剧增加对金黄色葡萄球菌 (S. aureus) 感染的治疗构成了巨大挑战。因此，迫切需要寻找新型抗感染药物来攻击新的靶点以克服抗生素耐药性。酪蛋白水解酶 P (ClpP) 是 S. aureus 维持细胞内稳态的关键毒力因子。我们从类黄酮中进行筛选，最终确定槲皮素可以有效削弱 MRSA 的毒力。热移位分析的结果表明，槲皮素可以与 ClpP 结合并降低 ClpP 的热稳定性，通过局部表面等离子体共振确定槲皮素与 ClpP 之间的 值为 197 nM。我们发现槲皮素在 MRSA 诱导的致命感染的小鼠模型中表现出保护作用。基于上述事实，作为 ClpP 抑制剂的槲皮素可以进一步开发为抗毒力药物的潜在候选药物，以对抗 S. aureus 感染。金黄色葡萄球菌 (S. aureus) 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。酪蛋白水解酶 P (ClpP) 是一种水解酶，已被证明可以调节 S. aureus 中的多种重要毒力因子。在这里，我们发现来自传统中草药类黄酮的小分子化合物槲皮素可有效抑制 ClpP 活性。槲皮素可减弱 S. aureus 中多种毒力因子的表达，并有效保护小鼠免受 MRSA 引起的致命性肺炎。总之，我们确定槲皮素是一种 ClpP 抑制剂，也是开发基于毒力因子的 S. aureus 感染治疗方法的有效先导化合物。
