Targeting quorum sensing and competence stimulation for antimicrobial chemotherapy.
Targeting quorum sensing and competence stimulation for antimicrobial chemotherapy.
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针对抗菌化疗的群体感应和能力刺激。
DOI：
10.2174/138945012803530233
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发表时间：
2012
影响因子：
3.2
通讯作者：
D. Fairlie
中科院分区：
文献类型：
--
作者：
Nicholas E. Shepherd;R. S. Harrison;D. Fairlie
细菌对抗生素的耐药性现在是一个严重的问题，传统类别的抗生素已经逐渐失效。因此，需要新的药物来靶向和抑制影响细菌生长的新途径。细菌生存的一个重要特征是它们作为一个群体通过分泌的自我诱导分子来协调它们的努力。能力刺激肽(CSP)是参与这种协调的群体感应信息素之一。这些多肽激活了革兰氏阴性细菌中的一个双组分系统，与一种名为Comd的组氨酸激酶受体结合并激活，该受体磷酸化了一种名为Come的反应调节因子，导致基因表达和能力诱导。有能力的细菌能够吸收外源DNA，并将其整合到自己的基因组中。通过这种机制，细菌能够获得并共享编码抗生素耐药性的基因。尽管已经研究了30多年，但作为一种调节细菌生长的新方法，这一途径直到最近才开始被探索。COMD的拮抗剂可能会阻止导致感受态的信号级联反应，而COMD的过度刺激也可能会减少细菌的生长。抑制COMD的一种可能的方法是检查激活COMD的CSPs的多肽序列，并试图将它们限制在生物活性构象上，由于受体的识别预先组织，可能具有更高的亲和力。因此，模拟CSPs的α螺旋表位的小分子，推定的COMD结合域，在这里已经被证明可以抑制细菌的生长，如肺炎链球菌。这种α螺旋模拟可能是利用一种新的机制控制细菌生长的抗菌化疗药物的有价值的线索。
Bacterial resistance to antibiotics is now a serious problem, with traditional classes of antibiotics having gradually become ineffective. New drugs are therefore needed to target and inhibit novel pathways that affect the growth of bacteria. An important feature in the survival of bacteria is that they coordinate their efforts together as a colony via secreted auto-inducing molecules. Competence stimulating peptides (CSPs) are among the quorum sensing pheromones involved in this coordination. These peptides activate a two-component system in gram-negative bacteria, binding to and activating a histidine kinase receptor called ComD, which phosphorylates a response regulator called ComE, leading to gene expression and induction of competence. Competent bacteria are able to take up exogenous DNA and incorporate it into their own genome. By this mechanism bacteria are able to acquire and share genes encoding antibiotic resistance. Despite having been studied for over 30 years, this pathway has only recently begun to be explored as a novel approach to modulating bacterial growth. Antagonists of ComD might block the signaling cascade that leads to competence, while overstimulation of ComD might also reduce bacterial growth. One possible approach to inhibiting ComD is to examine peptide sequences of CSPs that activate ComD and attempt to constrain them to bioactive conformations, likely to have higher affinity due to pre-organization for recognition by the receptor. Thus, small molecules that mimic an alpha helical epitope of CSPs, the putative ComD binding domain, have been shown here to inhibit growth of bacteria such as S. pneumoniae. Such alpha helix mimetics may be valuable clues to antibacterial chemotherapeutic agents that utilize a new mechanism to control bacterial growth.