Natural flavonoids disrupt bacterial iron homeostasis to potentiate colistin efficacy

作者：Zi-Xing Zhong, Shuang Zhou, Yu-jiao Liang, Yi-yang Wei, Yan Li, Tengfei Long, He Qian, Mengyuan Li, Yu‐Feng Zhou, Yang Yu, Liang‐Xing Fang, Xiao‐Ping Liao, Barry N. Kreiswirth, Liang Chen, Hao Ren, Ya-hong Liu, Jian Sun · 发表于：Science Advances · 年份：2023 · DOI：10.1126/sciadv.adg4205 · 被引用次数：118 · 研究领域：Antibiotic Resistance in Bacteria、Iron Metabolism and Disorders、Drug Transport and Resistance Mechanisms

In the face of the alarming rise in global antimicrobial resistance, only a handful of novel antibiotics have been developed in recent decades, necessitating innovations in therapeutic strategies to fill the void of antibiotic discovery. Here, we established a screening platform mimicking the host milieu to select antibiotic adjuvants and found three catechol-type flavonoids—7,8-dihydroxyflavone, myricetin, and luteolin—prominently potentiating the efficacy of colistin. Further mechanistic analysis demonstrated that these flavonoids are able to disrupt bacterial iron homeostasis through converting ferric iron to ferrous form. The excessive intracellular ferrous iron modulated the membrane charge of bacteria via interfering the two-component system pmrA / pmrB , thereby promoting the colistin binding and subsequent membrane damage. The potentiation of these flavonoids was further confirmed in an in vivo infection model. Collectively, the current study provided three flavonoids as colistin adjuvant to replenish our arsenals for combating bacterial infections and shed the light on the bacterial iron signaling as a promising target for antibacterial therapies.