Mechanism of inhibition of Bacillus anthracis spore outgrowth by the lantibiotic nisin.
Mechanism of inhibition of Bacillus anthracis spore outgrowth by the lantibiotic nisin.
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DOI：
10.1021/cb1004178
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发表时间：
2011-07-15
影响因子：
4
通讯作者：
van der Donk, Wilfred A.
中科院分区：
文献类型：
--
作者：
Gut, Ian M.;Blanke, Steven R.;van der Donk, Wilfred A.
羊毛硫抗生素乳链菌肽通过与脂质II结合来抑制营养期革兰氏阳性细菌的生长，脂质II破坏细胞壁的生物合成并促进孔的形成。乳链菌肽还抑制细菌孢子的生长，包括炭疽芽孢杆菌的孢子，其结构和生物化学性质与营养细菌的结构和生物化学性质根本不同。乳酸链球菌素抑制孢子生长的分子基础尚未确定，因为以前的研究表明，孢子生长的抑制涉及与孢子靶点的共价结合或膜完整性的丧失;尚未研究通过与脂质II结合破坏细胞壁生物合成。为了提供对后一种可能性的见解，将乳酸链球菌素的作用与万古霉素的作用进行了比较，万古霉素是另一种脂质II结合抗生素，其抑制细胞壁生物合成但不形成孔。乳酸链球菌素和万古霉素都抑制营养细胞的复制，但只有乳酸链球菌素抑制从萌发的孢子到营养细胞的过渡。此外，万古霉素阻止乳酸链球菌素的活性在竞争研究，表明乳酸链球菌素-脂质II的相互作用是重要的抑制孢子生长。在荧光标记乳酸链球菌素的实验中，没有发现抑制孢子生长的共价机制的证据。有趣的是，在铰链区的突变体（N20 P/M21 P和M21 P/K22 P），仍然结合脂质II，但不能形成孔对营养B具有有效的抗微生物活性。炭疽菌细胞，但不抑制孢子生长。因此，孔的形成是后者的活动，而不是前者必不可少的。总的来说，这些研究表明，乳链菌肽利用脂质II作为萌发孢子的目标生长抑制过程中，乳链菌肽介导的膜破坏是必不可少的抑制孢子发育成营养细胞。
The lantibiotic nisin inhibits growth of vegetative Gram-positive bacteria by binding to lipid II, which disrupts cell wall biosynthesis and facilitates pore formation. Nisin also inhibits the outgrowth of bacterial spores, including spores of Bacillus anthracis, whose structural and biochemical properties are fundamentally different from those of vegetative bacteria. The molecular basis of nisin inhibition of spore outgrowth had not been identified, as previous studies suggested that inhibition of spore outgrowth involved either covalent binding to a spore target or loss of membrane integrity; disruption of cell wall biosynthesis via binding to lipid II had not been investigated. To provide insights into the latter possibility, the effects of nisin were compared with those of vancomycin, another lipid II binding antibiotic that inhibits cell wall biosynthesis but does not form pores. Nisin and vancomycin both inhibited the replication of vegetative cells, but only nisin inhibited the transition from a germinated spore to a vegetative cell. Moreover, vancomycin prevented nisin’s activity in competition studies, suggesting that the nisin-lipid II interaction is important for inhibition of spore outgrowth. In experiments with fluorescently labeled nisin, no evidence was found for a covalent mechanism for inhibition of spore outgrowth. Interestingly, mutants in the hinge region (N20P/M21P and M21P/K22P) that still bind lipid II but cannot form pores had potent antimicrobial activity against vegetative B. anthracis cells but did not inhibit spore outgrowth. Therefore, pore formation is essential for the latter activity but not the former. Collectively, these studies suggest that nisin utilizes lipid II as the germinated spore target during outgrowth inhibition and that nisin-mediated membrane disruption is essential to inhibit spore development into vegetative cells.
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