Development of antipathogenic agents targeting biosynthetic enzyme and receptor of cyclic peptide quormone

开发针对生物合成酶和环肽Qurmone受体的抗病原体药物

基本信息

批准号：
21380061
负责人：
NAKAYAMA Jiro
金额：
$ 9.15万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21380061/
关键词：
微生物制御学クオラムセンシング腸球菌ブドウ球菌アンタゴニストペプチド合成放線菌二次代謝産物眼内炎クォーラムセンシングペプチドアンタゴニストクォルモンゼラチナーゼ抗感染症剤リバースアラニンスキャンポスト抗生物質

项目摘要

Quorum sensing with thiolactone or lactone peptide as an autoinducer is common among a number of Gram-positive bacteria and controls the expression of virulence in some pathogens, e. g., staphylococci, enterococci and listeria. In this context, the validity of anti-pathogenic agents targeting this type of quorum sensing has been proposed. In this study, to aim inhibitors targeting the cyclic peptide-mediated quorum sensing in Gram-positive bacteria, we have been employing two approaches, that are random screening of microbial secondary metabolites and drug design of peptide antagonists. For the screening, we have established an efficient screening system using an gelatinase assay of Enterococcus faecalis. Thus far, we have tested more than a thousand extracts of fungi and actinomycetes and more than a hundred natural and synthetic compounds and found several compounds to efficiently inhibit either or both staphylococci agr and enterococci fsr quorum sensing systems. For the design of p … More eptide antagonist, we took our original approach, called reverse alanine scanning, during which more potent antagonists were led step by step from receptor-binding scaffold that is[ Ala4, 5, 6, 8, 9, 11]] Z-GBAP(GBAP is an autoinducing lactone peptide of E. faecalis fsr system). In consequence, 5th, 9th and 11th residues in GBAP were found to be antagonist pharmacophore and with this information, we have eventually created a potent antagonist, named ZBzl-YAA5911(IC80=0. 1μM). To elucidate the availability of ZBzl-YAA5911 as an anti-infective agent, the efficacy of this peptide for endophthalmitis was assessed with an aphakic rabbit endophthalmitis model. As a result, ZBzl-YAA5911 suppressed the translocation of E. faecalis from the aqueous humor into the vitreous cavity more than one order magnitude and also significantly reduced the retinal damage of animals, suggesting that ZBzi-YAA5911 would be useful as anti-pathogenic agent to attenuate virulence expression more than eliminate the opportunistic pathogen. Less

使用硫内酯或内酯肽作为自诱导剂的群体感应在许多革兰氏阳性细菌中很常见，并控制某些病原体（例如葡萄球菌、肠球菌和李斯特菌）的毒力表达。在这项研究中，为了针对革兰氏阳性细菌中环肽介导的群体感应的抑制剂，我们提出了这种类型的群体感应。一直采用两种方法，即微生物次生代谢物的随机筛选和肽拮抗剂的药物设计。为了筛选，我们已经使用粪肠球菌的明胶酶测定建立了有效的筛选系统，到目前为止，我们已经测试了一千多种。真菌和放线菌的提取物以及一百多种天然和合成化合物，发现了几种化合物可以有效抑制葡萄球菌 agr 和肠球菌 fsr 群体感应系统或两者。对于 p 肽拮抗剂的设计，我们采用了最初的方法，称为反向丙氨酸扫描，在此过程中，从受体结合支架逐步引导出更有效的拮抗剂，即[ Ala4, 5, 6, 8, 9, 11 ]] Z-GBAP（GBAP是粪肠球菌fsr系统的自诱导内酯肽）因此，发现GBAP中的第5、9和11个残基是拮抗剂。药效基团并利用这些信息，我们最终创建了一种有效的拮抗剂，命名为 ZBzl-YAA5911（IC80=0. 1μM）。为了阐明 ZBzl-YAA5911 作为抗感染剂的可用性，评估了该肽对眼内炎的功效。结果，ZBzl-YAA5911 抑制了无晶状体兔眼内炎模型的易位。 E. faecalis 从房水进入玻璃体腔超过一个数量级，并且还显着减少了动物的视网膜损伤，这表明 ZBzi-YAA5911 可用作抗病原体剂，不仅可以消除机会病原体，还可以减弱毒力表达。较少的