Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II.
Turning defense into offense: defensin mimetics as novel antibiotics targeting lipid II.
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DOI：
10.1371/journal.ppat.1003732
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
de Leeuw EP
中科院分区：
文献类型：
--
作者：
Varney KM;Bonvin AM;Pazgier M;Malin J;Yu W;Ateh E;Oashi T;Lu W;Huang J;Diepeveen-de Buin M;Bryant J;Breukink E;Mackerell AD Jr;de Leeuw EP
我们以前曾报道过脂质II与人α-防御素，一类抗菌肽的功能相互作用。脂质II是细菌细胞壁生物合成的重要前体，也是天然抗生素化合物的理想和有效靶点。使用结构，功能和计算机分析的组合，我们在这里提出的防御素-脂质II结合的分子基础。基于脂质II与人神经肽-1的复合物，我们可以鉴定和表征化学上不同的低分子量化合物，其模拟HNP-1和脂质II之间的相互作用。进一步表征了先导化合物BAS 00127538的结构和功能;其与脂质II的N-乙酰胞壁酸部分和异戊二烯基尾特异性相互作用，靶向细胞壁合成，并在体内脓毒症模型中具有保护作用。我们首次鉴定并表征了以高特异性和亲和力靶向Lipid II的低分子量合成化合物。这些化合物的优化可以允许它们开发为用于治疗革兰氏阳性病原体感染的新的下一代治疗剂。每年，越来越多的人面临无法有效治疗的细菌感染风险。这是因为许多细菌对抗生素的耐药性越来越强。特别令人关切的是医院获得性感染的增加。由耐甲氧西林金黄色葡萄球菌（MRSA）引起的感染是许多死亡的原因，并给许多国家的卫生保健系统带来负担。治疗S.在金黄色葡萄球菌感染中，万古霉素是一种抗微生物肽，其通过与细菌细胞壁组分脂质II结合来杀死细菌。在这里，我们首次发现了与Lipid II结合的小合成化合物，旨在开发新的抗生素药物来对抗细菌感染。
We have previously reported on the functional interaction of Lipid II with human alpha-defensins, a class of antimicrobial peptides. Lipid II is an essential precursor for bacterial cell wall biosynthesis and an ideal and validated target for natural antibiotic compounds. Using a combination of structural, functional and in silico analyses, we present here the molecular basis for defensin-Lipid II binding. Based on the complex of Lipid II with Human Neutrophil peptide-1, we could identify and characterize chemically diverse low-molecular weight compounds that mimic the interactions between HNP-1 and Lipid II. Lead compound BAS00127538 was further characterized structurally and functionally; it specifically interacts with the N-acetyl muramic acid moiety and isoprenyl tail of Lipid II, targets cell wall synthesis and was protective in an in vivo model for sepsis. For the first time, we have identified and characterized low molecular weight synthetic compounds that target Lipid II with high specificity and affinity. Optimization of these compounds may allow for their development as novel, next generation therapeutic agents for the treatment of Gram-positive pathogenic infections. Every year, an increasing number of people are at risk for bacterial infections that cannot be effectively treated. This is because many bacteria are becoming more resistant to antibiotics. Of particular concern is the rise in hospital-acquired infections. Infection caused by the methicillin-resistant Staphylococcus aureus bacterium or MRSA is the cause of many fatalities and puts a burden on health care systems in many countries. The antibiotic of choice for treatment of S. aureus infections is vancomycin, an antimicrobial peptide that kills bacteria by binding to the bacterial cell wall component Lipid II. Here, we have identified for the first time, small synthetic compounds that also bind Lipid II with the aim to develop new antibiotic drugs to fight against bacterial infections.
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影响因子：
11.8
作者：
Ihi, T;Nakazato, M;Matsukura, S
通讯作者：
Matsukura, S
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
DOI：
10.1111/j.1432-1033.1997.t01-1-00193.x
发表时间：
1997-05-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Brotz, H;Bierbaum, G;Sahl, HG
通讯作者：
Sahl, HG
影响因子：
3.9
作者：
Bevins, CL
通讯作者：
Bevins, CL