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Science:可抑制细菌细胞壁的形成的防御素

528日,《科学》杂志报道称,某些真菌用一种防御性的肽,或称防御素,来击退细菌,这种防御素实际上抑制了细菌细胞壁的形成,而不是像其它的防御素那样简单地破坏了细菌的细胞膜。

        将来,这一发现可为抗菌药物的研发提供新的而且有效的标靶。 Tanja Schneider及其同僚对一种特别的真菌防御素菌丝霉素(plectasin)做了无数的遗传学和生物化学研究,并发现它可直接与Lipid II(这是细菌细胞壁的一个基本成分)结合。

        研究人员还利用了核磁共振NMR)加上电脑模型来寻找菌丝霉素中的与Lipid II结合的关键残基。 因为菌丝霉素具有抗某些耐药性格兰氏阳性细菌的活性,而且研究人员过去曾经在无脊椎动物中找到另外2种以Lipid II为标靶的防御素,因此这一发现可能会在将来被用于发现更多有效的抗菌药物。

原文出处:

Science  DOI: 10.1126/science.1185723

Plectasin, a Fungal Defensin, Targets the Bacterial Cell Wall Precursor Lipid II
Tanja Schneider,1 Thomas Kruse,2 Reinhard Wimmer,3 Imke Wiedemann,1 Vera Sass,1 Ulrike Pag,1 Andrea Jansen,1 Allan K. Nielsen,4 Per H. Mygind,4 Dorotea S. Raventós,4 S?ren Neve,4 Birthe Ravn,4 Alexandre M. J. J. Bonvin,5 Leonardo De Maria,4 Anders S. Andersen,2,4 Lora K. Gammelgaard,4 Hans-Georg Sahl,1 Hans-Henrik Kristensen4,*

Host defense peptides such as defensins are components of innate immunity and have retained antibiotic activity throughout evolution. Their activity is thought to be due to amphipathic structures, which enable binding and disruption of microbial cytoplasmic membranes. Contrary to this, we show that plectasin, a fungal defensin, acts by directly binding the bacterial cell-wall precursor Lipid II. A wide range of genetic and biochemical approaches identify cell-wall biosynthesis as the pathway targeted by plectasin. In vitro assays for cell-wall synthesis identified Lipid II as the specific cellular target. Consistently, binding studies confirmed the formation of an equimolar stoichiometric complex between Lipid II and plectasin. Furthermore, key residues in plectasin involved in complex formation were identified using nuclear magnetic resonance spectroscopy and computational modeling.

1 Pharmaceutical Microbiology Section, Institute for Medical Microbiology, Immunology, and Parasitology, University of Bonn, D-53115 Bonn, Germany.
2 Statens Serum Institut, 2300 Copenhagen S, Denmark.
3 Department of Biotechnology, Chemistry, and Environmental Engineering, Aalborg University, DK-9000 Aalborg, Denmark.
4 Novozymes AS, DK-2880 Bagsvaerd, Denmark.
5 Department of Chemistry, Faculty of Science, Utrecht University, 3584 CH Utrecht, Netherlands.