Development of xanthone derivatives as effective broad-spectrum antimicrobials: Disrupting cell wall and inhibiting DNA synthesis

Discovering potent antibiotics is of critical importance due to the
substantial increases of microbial resistance. Xanthones are intriguing
sources of antimicrobials, despite a scarcity of extensive investigations
into their mechanisms of action. Here, we reported the development of a
series of xanthone derivatives, among which compound XT17 displayed strong
broad-spectrum antibacterial activity, weak hemolytic activity and low
cytotoxicity against mammalian cell lines, low frequencies of drug
resistance, and potent in vivo efficacy in Staphylococcu aureus or
Pseudomonas aeruginosa induced murine corneal infection models. Compound
XT17 presented a multifaceted mode of actions, involving the disruption of
cell wall by interacting with lipoteichoic acid or lipopolysaccharides and
the suppression of DNA synthesis. A further docking study confirmed the
capability of compound XT17 to form a stable complex with the bacterial
gyrase enzyme. This work could offer an innovative design strategy for
developing broad-spectrum therapeutic agents against drug-resistant
bacteria.

由于微生物耐药性持续攀升，研发强效抗生素的重要性愈发凸显。呫吨酮类化合物（xanthones）是颇具潜力的抗菌药物来源，但其作用机制尚未得到充分深入的研究。本研究报道了一系列呫吨酮衍生物的开发工作，其中化合物XT17展现出强效广谱抗菌活性，仅表现出微弱溶血活性与对哺乳动物细胞系的低细胞毒性，且耐药突变频率极低；在金黄色葡萄球菌（Staphylococcu aureus）或铜绿假单胞菌（Pseudomonas aeruginosa）诱导的小鼠角膜感染模型中，该化合物同样展现出优异的体内抗菌疗效。化合物XT17的抗菌作用机制具有多靶点特征：可通过与脂磷壁酸（lipoteichoic acid）或脂多糖（lipopolysaccharides）结合破坏细菌细胞壁，并抑制DNA合成。后续分子对接研究证实，化合物XT17可与细菌DNA旋转酶形成稳定复合物。本研究可为抗耐药菌广谱治疗药物的开发提供全新的设计策略。