Peziculone 抗革兰氏阳性菌的活性及其作用机制探究

目前，由耐药革兰氏阳性细菌引起的医院血流感染现象频发，导致感染患者的发病率和死亡率显著增加，迫切需要优化抗生素的使用，并不断开发新的抗菌药来对抗耐药性。遗憾的是，近年来只有少数几种新的对耐药革兰氏阳性细菌有效的抗生素被开发和批准。地衣酸是一种具有代表性的二苯并呋喃代谢物，具有抗革兰氏阳性菌活性但应用不佳，因此，寻找比地衣酸活性更好且安全性更高的地衣酸衍生物一直是众多学者的研究目标。

本研究描述了一种新型高得率地衣酸衍生物—peziculone，它由两个不可分离的结构peziculone A和peziculone B以5：1的比例混合而成。通过抑菌圈实验结合最低浓度抑制实验，证明了peziculone对几种革兰氏阳性细菌的抗菌活性明显优于地衣酸，达到现有抗生素药物效果，十分具有开发潜力。为了探究peziculone抗革兰氏阳性菌的作用靶点及机制，通过定向进化实验、基因组测序、CRISPRi-seq等一系列系统生物学方法，发现了peziculone的多个抗菌基因位点，生物信息学分析推测peziculone主要靶向细胞壁的合成通路及必要的代谢通路。后续利用细胞壁荧光染色方法，证实了peziculone通过破坏革兰氏阳性菌细胞壁的稳定性从而达到快速抗菌效果。此外，结合扫描电镜和结晶紫染色法，本研究进一步发现，亚抑菌浓度的peziculone处理会损害金黄色葡萄球菌的细胞表面附属物和生物被膜的形成，避免了细菌的免疫逃逸定植。

综上所述，地衣酸衍生物peziculone可以通过靶向细胞壁和生物被膜显著抑制金黄色葡萄球菌等革兰氏阳性菌，有希望开发成为一款新型抗革兰氏阳性菌药物，并为其它抗菌药物的研发拓展了思路。

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