Zeng Jiahao, Iizaka Yohei, Ouchi Yasuhiro, Otsuki Kouharu, Kikuchi Takashi, Li Wei, Anzai Yojiro
Faculty of Pharmaceutical Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 274-8510, Japan.
J Nat Med. 2025 May;79(3):608-620. doi: 10.1007/s11418-025-01902-w. Epub 2025 Apr 8.
Pseudomonas aeruginosa is an opportunistic human pathogen that causes a wide range of infections. The increasing multidrug-resistance of P. aeruginosa poses a critical challenge for medical care. P. aeruginosa employs virulence factors and biofilms to establish infections in humans and protect itself from environmental stress or antibiotics. These factors are regulated by a quorum sensing mechanism involving multiple regulatory systems that act interdependently through signaling molecules. Therefore, interference with quorum sensing systems can suppress the pathogenicity of P. aeruginosa. In this study, quorum sensing inhibitors were explored from secondary metabolites derived from 111 strains of actinomycetes by targeting the las system, which is thought to be upstream of the quorum sensing cascade in P. aeruginosa. As a result, reumycin was isolated from the culture broth of Streptomyces sp. TPMA0082. Reumycin, a molecule containing a pyrimidotriazine ring, inhibited the binding of the autoinducer to the LasR receptor in the las system, thereby suppressing the production of P. aeruginosa virulence factors, including pyocyanin, rhamnolipids, elastase, motility, and biofilms, without affecting bacterial growth. Toxoflavin, a reumycin derivative with a methyl group at the N1 position, exhibited strong antibacterial activity. Fervenulin, a reumycin derivative with a methyl group at the N8 position, had a negative impact on the logarithmic growth phase of the bacteria and exhibited lower inhibitory activity against virulence factor production compared to reumycin. These findings suggest that the position and number of methyl groups attached to the pyrimidotriazine structure significantly influence its biological activity, exerting distinct effects on quorum sensing inhibition and antibacterial activity.
铜绿假单胞菌是一种机会性人类病原体，可引发多种感染。铜绿假单胞菌日益增强的多重耐药性对医疗护理构成了严峻挑战。铜绿假单胞菌利用毒力因子和生物膜在人体内建立感染，并保护自身免受环境压力或抗生素的影响。这些因子由群体感应机制调控，该机制涉及多个调控系统，这些系统通过信号分子相互依存地发挥作用。因此，干扰群体感应系统可抑制铜绿假单胞菌的致病性。在本研究中，通过靶向被认为是铜绿假单胞菌群体感应级联上游的las系统，从111株放线菌的次生代谢产物中探索群体感应抑制剂。结果，从链霉菌属TPMA0082的培养液中分离出了鲁霉素。鲁霉素是一种含有嘧啶三嗪环的分子，它抑制自体诱导物与las系统中LasR受体的结合，从而抑制铜绿假单胞菌毒力因子的产生，包括绿脓菌素、鼠李糖脂、弹性蛋白酶、运动性和生物膜，而不影响细菌生长。毒黄素是一种在N1位置带有甲基的鲁霉素衍生物，具有很强的抗菌活性。 fervenulin是一种在N8位置带有甲基的鲁霉素衍生物，对细菌的对数生长期有负面影响，并且与鲁霉素相比，对毒力因子产生的抑制活性较低。这些发现表明，连接到嘧啶三嗪结构上的甲基的位置和数量显著影响其生物活性，对群体感应抑制和抗菌活性产生不同的影响。
