School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic of Korea.
Appl Microbiol Biotechnol. 2013 May;97(10):4543-52. doi: 10.1007/s00253-012-4674-z. Epub 2013 Jan 15.
Human pathogens can readily develop drug resistance due to the long-term use of antibiotics that mostly inhibit bacterial growth. Unlike antibiotics, antivirulence compounds diminish bacterial virulence without affecting cell viability and thus, may not lead to drug resistance. Staphylococcus aureus is a major agent of nosocomial infections and produces diverse virulence factors, such as the yellow carotenoid staphyloxanthin, which promotes resistance to reactive oxygen species (ROS) and the host immune system. To identify novel antivirulence compounds, bacterial signal indole present in animal gut and diverse indole derivatives were investigated with respect to reducing staphyloxanthin production and the hemolytic activity of S. aureus. Treatment with indole or its derivative 7-benzyloxyindole (7BOI) caused S. aureus to become colorless and inhibited its hemolytic ability without affecting bacterial growth. As a result, S. aureus was more easily killed by hydrogen peroxide (H₂O₂) and by human whole blood in the presence of indole or 7BOI. In addition, 7BOI attenuated S. aureus virulence in an in vivo model of nematode Caenorhabditis elegans, which is readily infected and killed by S. aureus. Transcriptional analyses showed that both indole and 7BOI repressed the expressions of several virulence genes such as α-hemolysin gene hla, enterotoxin seb, and the protease genes splA and sspA and modulated the expressions of the important regulatory genes agrA and sarA. These findings show that indole derivatives are potential candidates for use in antivirulence strategies against persistent S. aureus infection.
由于长期使用抗生素，抗生素主要抑制细菌生长，人类病原体很容易产生耐药性。与抗生素不同，抗毒化合物在不影响细胞活力的情况下降低细菌的毒力，因此可能不会导致耐药性。金黄色葡萄球菌是医院感染的主要病原体，产生多种毒力因子，如黄色类胡萝卜素金黄色素，它促进了对活性氧（ROS）和宿主免疫系统的抗性。为了鉴定新的抗毒化合物，研究了动物肠道中的细菌信号吲哚和多种吲哚衍生物，以减少金黄色素的产生和金黄色葡萄球菌的溶血活性。吲哚或其衍生物 7-苄氧基吲哚（7BOI）处理使金黄色葡萄球菌变为无色，并抑制其溶血能力，而不影响细菌生长。结果，在有吲哚或 7BOI 的情况下，金黄色葡萄球菌更容易被过氧化氢（H₂O₂）和人全血杀死。此外，7BOI 在秀丽隐杆线虫（C. elegans）体内模型中减弱了金黄色葡萄球菌的毒力，该模型很容易被金黄色葡萄球菌感染和杀死。转录分析表明，吲哚和 7BOI 均抑制了几种毒力基因的表达，如α-溶血素基因 hla、肠毒素 seb、蛋白酶基因 splA 和 sspA，并调节了重要调节基因 agrA 和 sarA 的表达。这些发现表明，吲哚衍生物是针对持续性金黄色葡萄球菌感染的抗毒策略的潜在候选物。
