Norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant Staphylococcus aureus to β-lactam antibiotics.
Norgestimate inhibits staphylococcal biofilm formation and resensitizes methicillin-resistant Staphylococcus aureus to β-lactam antibiotics.
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DOI：
10.1038/s41522-017-0026-1
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发表时间：
2017
影响因子：
9.2
通讯作者：
Mizunoe Y
中科院分区：
文献类型：
--
作者：
Yoshii Y;Okuda KI;Yamada S;Nagakura M;Sugimoto S;Nagano T;Okabe T;Kojima H;Iwamoto T;Kuwano K;Mizunoe Y
医疗器械上细菌生物膜的形成可导致严重或致命的传染病。特别是，由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应答具有强烈的抗性。除了外科手术取出受污染的医疗器械并随后进行抗生素治疗外，没有有效的治疗方法来治疗生物膜相关感染。在这里，我们发现诺孕酯，一种乙酰化的葡萄球菌蛋白，有效地抑制葡萄球菌菌株，包括耐甲氧西林的S。金黄色葡萄球菌，而不抑制其生长，降低抗性出现的选择压力。17-诺孕酯的代谢产物去乙酰诺孕酯对葡萄球菌生物膜形成的抑制活性弱得多，表明诺孕酯的乙酰基对其活性很重要。诺孕酯通过抑制细胞外基质中多糖细胞间粘附素和蛋白质的产生来抑制葡萄球菌生物膜的形成。S.金黄色葡萄球菌的研究表明，诺孕酯抑制细胞壁锚定蛋白SasG的表达，其促进细胞间粘附，以及抑制糖酵解酶烯醇化酶的表达，其在生物膜形成中起次要作用。值得注意的是，诺孕酯诱导细胞壁形态的显着变化，其特征在于厚度增加和异常波纹隔膜。此外，诺孕酯增加青霉素结合蛋白2的表达水平，并使耐甲氧西林的S.金黄色葡萄球菌对β-内酰胺类抗生素的敏感性。这些结果表明，诺孕酯是一种有前途的先导化合物，用于开发治疗生物膜相关感染的药物，以及其使耐甲氧西林的S.金黄色葡萄球菌对β-内酰胺类抗生素的敏感性。一种与孕酮激素相关的合成分子可能会使医疗设备免受生物膜的影响，而不会促进抗生素耐药性。已被生物膜污染的植入器械通常必须在用抗生素治疗潜在感染之前通过手术取出。东京Jikei大学医学院的Ken-ichi Okuda及其同事与日本其他地方的同事发现，合成孕酮类似物诺孕酯抑制生物膜的形成，而不抑制细菌生长。他们认为这种对生物膜形成的选择性作用是一个显著的优势，因为它降低了在目标细菌中诱导耐药性的风险。他们使用葡萄球菌证明了这种效果，包括有问题和高度危险的耐甲氧西林金黄色葡萄球菌（MRSA）。该研究还表明，诺孕酯可以使MRSA细菌对它们耐药的一些抗生素重新敏感。
Formation of bacterial biofilms on medical devices can cause severe or fatal infectious diseases. In particular, biofilm-associated infections caused by methicillin-resistant Staphylococcus aureus 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 S. aureus, 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 S. aureus 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 S. aureus 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 S. aureus to β-lactam antibiotics. A synthetic molecule related to the hormone progesterone might keep medical devices free of biofilms without promoting antibiotic resistance. Implanted devices that have become contaminated with biofilms generally must be surgically removed prior to treating the underlying infection with antibiotics. Ken-ichi Okuda and colleagues at The Jikei University School of Medicine in Tokyo, with co-workers elsewhere in Japan, found that the synthetic progesterone analog norgestimate inhibits biofilm formation without inhibiting bacterial growth. They regard this selective effect on biofilm formation as a significant advantage, as it reduces the risk of inducing resistance in the targeted bacteria. They demonstrated the effect using staphylococcal bacteria, including the problematic and highly dangerous methicillin-resistant Staphylococcus aureus (MRSA). The research also indicated that norgestimate can resensitize MRSA bacteria to some of the antibiotics they are resistant to.
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影响因子：
5.7
作者：
Chiba A;Sugimoto S;Sato F;Hori S;Mizunoe Y
通讯作者：
Mizunoe Y
影响因子：
3.1
作者：
Cramton, SE;Gerke, C;Götz, F
通讯作者：
Götz, F
影响因子：
5.8
作者：
Carneiro, CRW;Postol, E;Brentani, RR
通讯作者：
Brentani, RR
影响因子：
9.4
作者：
Ceri, H;Olson, ME;Buret, A
通讯作者：
Buret, A
影响因子：
3.6
作者：
Heilmann, C;Schweitzer, O;Gotz, F
通讯作者：
Gotz, F