Yoshii Yutaka, Okuda Ken-Ichi, Yamada Satomi, Nagakura Mari, Sugimoto Shinya, Nagano Tetsuo, Okabe Takayoshi, Kojima Hirotatsu, Iwamoto Takeo, Kuwano Kazuyoshi, Mizunoe Yoshimitsu
Department of Bacteriology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461 Japan.
Jikei Center for Biofilm Science and Technology, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461 Japan.
NPJ Biofilms Microbiomes. 2017 Jul 21;3:18. doi: 10.1038/s41522-017-0026-1. eCollection 2017.
Formation of bacterial biofilms on medical devices can cause severe or fatal infectious diseases. In particular, biofilm-associated infections caused by methicillin-resistant are difficult to eradicate because the biofilm is strongly resistant to antibiotics and the host immune response. There is no effective treatment for biofilm-associated infectionss, except for surgical removal of contaminated medical devices followed by antibiotic therapy. Here we show that norgestimate, an acetylated progestin, effectively inhibits biofilm formation by staphylococcal strains, including methicillin-resistant , without inhibiting their growth, decreasing the selective pressure for emergence of resistance. 17-Deacetyl norgestimate, a metabolite of norgestimate, shows much weaker inhibitory activity against staphylococcal biofilm formation, indicating that the acetyl group of norgestimate is important for its activity. Norgestimate inhibits staphylococcal biofilm formation by inhibiting production of polysaccharide intercellular adhesin and proteins in the extracellular matrix. Proteome analysis of . indicated that norgestimate represses the expression of the cell wall-anchored protein SasG, which promotes intercellular adhesion, and of the glycolytic enzyme enolase, which plays a secondary role in biofilm formation. Notably, norgestimate induces remarkable changes in cell wall morphology, characterized by increased thickness and abnormal rippled septa. Furthermore, norgestimate increases the expression level of penicillin binding protein 2 and resensitizes methicillin-resistant to β-lactam antibiotics. These results suggest that norgestimate is a promising lead compound for the development of drugs to treat biofilm-associated infections, as well as for its ability to resensitize methicillin-resistant to β-lactam antibiotics.
医疗设备上细菌生物膜的形成可导致严重或致命的传染病。特别是，耐甲氧西林金黄色葡萄球菌引起的生物膜相关感染难以根除，因为生物膜对抗生素和宿主免疫反应具有很强的抗性。除了手术移除受污染的医疗设备并随后进行抗生素治疗外，对于生物膜相关感染没有有效的治疗方法。在此我们表明，去氧孕烯炔雌醇，一种乙酰化孕激素，可有效抑制包括耐甲氧西林金黄色葡萄球菌在内的葡萄球菌菌株形成生物膜，而不抑制其生长，降低了耐药性出现的选择压力。去氧孕烯炔雌醇的代谢产物17-去乙酰去氧孕烯炔雌醇对葡萄球菌生物膜形成的抑制活性要弱得多，这表明去氧孕烯炔雌醇的乙酰基对其活性很重要。去氧孕烯炔雌醇通过抑制细胞间多糖黏附素和细胞外基质中蛋白质的产生来抑制葡萄球菌生物膜的形成。对耐甲氧西林金黄色葡萄球菌的蛋白质组分析表明，去氧孕烯炔雌醇可抑制促进细胞间黏附的细胞壁锚定蛋白SasG以及在生物膜形成中起次要作用的糖酵解酶烯醇化酶的表达。值得注意的是，去氧孕烯炔雌醇会引起细胞壁形态的显著变化，其特征是厚度增加和隔膜出现异常波纹。此外，去氧孕烯炔雌醇会增加青霉素结合蛋白2的表达水平，并使耐甲氧西林金黄色葡萄球菌对β-内酰胺类抗生素重新敏感。这些结果表明，去氧孕烯炔雌醇是开发治疗生物膜相关感染药物的有前景的先导化合物，同时也因其能使耐甲氧西林金黄色葡萄球菌对β-内酰胺类抗生素重新敏感。
