Karaolis David K R, Rashid Mohammed H, Chythanya Rajanna, Luo Wensheng, Hyodo Mamoru, Hayakawa Yoshihiro
Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Antimicrob Agents Chemother. 2005 Mar;49(3):1029-38. doi: 10.1128/AAC.49.3.1029-1038.2005.
Staphylococcus aureus is an important pathogen of humans and animals, and antibiotic resistance is a public health concern. Biofilm formation is essential in virulence and pathogenesis, and the ability to resist antibiotic treatment results in difficult-to-treat and persistent infections. As such, novel antimicrobial approaches are of great interest to the scientific, medical, and agriculture communities. We recently proposed that modulating levels of the cyclic dinucleotide signaling molecule, c-di-GMP (cyclic diguanylate [3',5'-cyclic diguanylic acid], cGpGp), has utility in regulating phenotypes of prokaryotes. We report that extracellular c-di-GMP shows activity against human clinical and bovine intramammary mastitis isolates of S. aureus, including methicillin-resistant S. aureus (MRSA) isolates. We show that chemically synthesized c-di-GMP is soluble and stable in water and physiological saline and stable following boiling and exposure to acid and alkali. Treatment of S. aureus with extracellular c-di-GMP inhibited cell-to-cell (intercellular) adhesive interactions in liquid medium and reduced (>50%) biofilm formation in human and bovine isolates compared to untreated controls. c-di-GMP inhibited the adherence of S. aureus to human epithelial HeLa cells. The cyclic nucleotide analogs cyclic GMP and cyclic AMP had a lesser inhibitory effect on biofilms, while 5'-GMP had no major effect. We propose that cyclic dinucleotides such as c-di-GMP, used either alone or in combination with other antimicrobial agents, represent a novel and attractive approach in the development of intervention strategies for the prevention of biofilms and the control and treatment of infection.
金黄色葡萄球菌是人和动物的重要病原体，抗生素耐药性是一个公共卫生问题。生物膜形成在毒力和发病机制中至关重要，而抵抗抗生素治疗的能力会导致难以治疗的持续性感染。因此，新型抗菌方法引起了科学界、医学界和农业界的极大兴趣。我们最近提出，调节环状二核苷酸信号分子c-di-GMP（环二鸟苷酸[3',5'-环二鸟苷酸]，cGpGp）的水平在调节原核生物表型方面具有实用价值。我们报告称，细胞外c-di-GMP对人临床分离株和牛乳房内乳腺炎分离株金黄色葡萄球菌具有活性，包括耐甲氧西林金黄色葡萄球菌（MRSA）分离株。我们表明，化学合成的c-di-GMP在水和生理盐水中可溶且稳定，在煮沸以及暴露于酸和碱后仍保持稳定。用细胞外c-di-GMP处理金黄色葡萄球菌可抑制液体培养基中细胞间（细胞与细胞之间）的黏附相互作用，与未处理的对照相比，可减少人源和牛源分离株中生物膜的形成（>50%）。c-di-GMP抑制金黄色葡萄球菌对人上皮HeLa细胞的黏附。环状核苷酸类似物环鸟苷酸和环腺苷酸对生物膜的抑制作用较小，而5'-鸟苷酸没有主要影响。我们提出，诸如c-di-GMP之类的环状二核苷酸单独使用或与其他抗菌剂联合使用，代表了一种在开发预防生物膜以及控制和治疗感染的干预策略方面新颖且有吸引力的方法。
