The nonantibiotic small molecule cyslabdan enhances the potency of β-lactams against MRSA by inhibiting pentaglycine interpeptide bridge synthesis.
The nonantibiotic small molecule cyslabdan enhances the potency of β-lactams against MRSA by inhibiting pentaglycine interpeptide bridge synthesis.
复制标题
DOI：
10.1371/journal.pone.0048981
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tomoda H
中科院分区：
文献类型：
--
作者：
Koyama N;Tokura Y;Münch D;Sahl HG;Schneider T;Shibagaki Y;Ikeda H;Tomoda H
链霉菌产生的非抗生素小分子天冬氨酸，是一种拉丹型二萜。K04-0144可显著增强β-内酰胺类药物亚胺培南对耐甲氧西林金黄色葡萄球菌的抗菌活性。为了研究Cyslabdan的作用机制，在MRSA裂解物中研究了与Cyslabdan结合的蛋白质，从而鉴定了FEMA，FEMA参与了MRSA肽聚糖五甘氨酸肽间桥的合成。此外，与FemB和FemX的结合分析表明，Cyslabdan与FemB有亲和力，而与FemX没有亲和力。在基于酶的分析中，Cyslabdan抑制FEMA活性，而As不影响FemX和FemB活性。Cyslabdan在MRSA细胞壁的肽聚糖中积累了非甘氨酰和单甘氨酰毛霉素类单体。这些发现表明，Cyslabdan主要抑制FEMA，从而抑制五甘氨酸多肽桥的合成。该蛋白是决定耐甲氧西林金黄色葡萄球菌对β-内酰胺类抗生素耐药性的关键因素，我们的发现为对抗耐甲氧西林金黄色葡萄球菌提供了一种新的策略。
The nonantibiotic small molecule cyslabdan, a labdan-type diterpene produced by Streptomyces sp. K04-0144, markedly potentiated the activity of the β-lactam drug imipenem against methicillin-resistant Staphylococcus aureus (MRSA). To study the mechanism of action of cyslabdan, the proteins that bind to cyslabdan were investigated in an MRSA lysate, which led to the identification of FemA, which is involved in the synthesis of the pentaglycine interpeptide bridge of the peptidoglycan of MRSA. Furthermore, binding assay of cyslabdan to FemB and FemX with the function similar to FemA revealed that cyslabdan had an affinity for FemB but not FemX. In an enzyme-based assay, cyslabdan inhibited FemA activity, where as did not affected FemX and FemB activities. Nonglycyl and monoglycyl murein monomers were accumulated by cyslabdan in the peptidoglycan of MRSA cell walls. These findings indicated that cyslabdan primarily inhibits FemA, thereby suppressing pentaglycine interpeptide bridge synthesis. This protein is a key factor in the determination of β-lactam resistance in MRSA, and our findings provide a new strategy for combating MRSA.
登录
查看更多内容
影响因子：
4.9
作者：
Malouin, F;Blais, J;Dudley, MN
通讯作者：
Dudley, MN
影响因子：
4.9
作者：
Zhao, WH;Hu, ZQ;Shimamura, T
通讯作者：
Shimamura, T
影响因子：
2.8
作者：
Rohrer, S;Berger-Bächi, B
通讯作者：
Berger-Bächi, B
影响因子：
3.2
作者：
Stranden, AM;Ehlert, K;BergerBachi, B
通讯作者：
BergerBachi, B
影响因子：
--
作者：
Huber, Joann;Donald, Robert G. K.;Roemer, Terry
通讯作者：
Roemer, Terry