Targeting extracellular pyrophosphates underpins the high selectivity of nisin
Targeting extracellular pyrophosphates underpins the high selectivity of nisin
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DOI：
10.1096/fj.04-2358com
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发表时间：
2004-12-01
期刊：
影响因子：
4.8
通讯作者：
Watts, A
中科院分区：
文献类型：
--
作者：
Bonev, BB;Breukink, E;Watts, A
传染病的蔓延和抗生素耐药性的增加代表着威胁生命的全球发展，需要新的方法来控制微生物。在所有潜在的靶点中，以已知的第一种抗生素青霉素为靶点的细菌细胞壁合成的基本和独特的途径，仍然是开发新抗生素的完美候选者。在这里，我们展示了抗生素Nisin通过靶向肽聚糖中间体的胞外焦磷酸发挥其抗菌作用，焦磷酸是细菌细胞壁前体所特有的。我们发现，Nisin将细菌质膜外层小叶中的细胞壁前体--Lipid II和十一碳烯基焦磷酸--隔离成稳定的复合体。我们提出了一个乳链菌素的抗菌作用模型，其中Ile1的末端氨基针对细菌细胞壁前体的焦磷酸基团，它通过氢键对接在那里。焦磷酸部分是一种高度保守的化学基团，不同于L-赖氨酸-D-丙氨酸-D-丙氨酸对接万古霉素基序，没有具有可比性质的生化类似物，不太可能对细菌适应敏感，类似于导致青霉素和万古霉素耐药的细菌适应。
The spread of infectious diseases and the increase in antibiotic resistance represent a life-threatening global development that calls for new approaches to control microorganisms. Of all potential targets, the essential and unique pathway of bacterial cell wall synthesis, targeted by the first known antibiotic penicillin, remains a perfect candidate for the development of new antibiotics. Here we show that the lantibiotic nisin exercises its antibacterial action by targeting peptidoglycan intermediates' extracellular pyrophosphate, unique to bacterial cell wall precursors. We show that nisin sequesters cell wall precursors found in the outer leaflet of bacterial plasma membranes, Lipid II and undecaprenyl pyrophosphate, into stable complexes. We propose a model of antibacterial action for nisin in which the terminal amino group of Ile1 targets the pyrophosphate groups of the bacterial cell wall precursors, where it docks via a hydrogen bond. The pyrophosphate moiety, a highly conserved chemical group different from the L-Lys-D-Ala-D-Ala docking motif for vancomycin, has no biochemical analogs with comparable properties and is unlikely to be susceptible to bacterial adaptations akin to those responsible for resistance to penicillins and vancomycin.