Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus.
Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus.
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DOI：
10.1186/1752-0509-5-68
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发表时间：
2011-05-12
影响因子：
--
通讯作者：
Coote PJ
中科院分区：
文献类型：
--
作者：
Overton IM;Graham S;Gould KA;Hinds J;Botting CH;Shirran S;Barton GJ;Coote PJ
金黄色葡萄球菌是一种主要的人类病原体，对现有治疗方法产生耐药性的菌株不断出现。因此，开发新的治疗方法很重要。抗菌肽是对抗耐甲氧西林金黄色葡萄球菌 (MRSA) 等耐药细菌的潜在新型抗生素的来源。雷那克辛（ranalexin）是一种很有前景的抗菌肽，它对革兰氏阳性菌，特别是金黄色葡萄球菌具有有效的活性。了解作用模式是药物发现的关键组成部分，网络生物学方法可以对微生物生理学（包括抗生素杀灭机制）产生全局、综合的看法。我们开发了一种全系统功能关联网络方法来整合蛋白质组和转录组图谱，从而能够研究耐药性和作用模式。通过贝叶斯逻辑回归构建功能关联网络，为从金黄色葡萄球菌 MRSA-252 转录组和蛋白质组分析中识别抗菌肽（ranalexin）反应模块提供了框架。雷那克辛治疗的这些特征揭示了多种杀伤机制，包括细胞壁活性。细胞壁效应得到基因破坏和渗透脆性实验的支持。此外，还推断出 22 个新的毒力因子，而 VraRS 双组分系统和 PhoU 介导的持续细胞形成与 MRSA 对阳离子抗菌肽的耐受性有关。这项工作展示了研究耐药性和作用方式的强大综合方法。我们的研究结果对于针对金黄色葡萄球菌，特别是耐甲氧西林金黄色葡萄球菌（MRSA）的新型治疗策略的开发提供了信息。
Staphylococcus aureus is a major human pathogen and strains resistant to existing treatments continue to emerge. Development of novel treatments is therefore important. Antimicrobial peptides represent a source of potential novel antibiotics to combat resistant bacteria such as Methicillin-Resistant Staphylococcus aureus (MRSA). A promising antimicrobial peptide is ranalexin, which has potent activity against Gram-positive bacteria, and particularly S. aureus. Understanding mode of action is a key component of drug discovery and network biology approaches enable a global, integrated view of microbial physiology, including mechanisms of antibiotic killing. We developed a systems-wide functional association network approach to integrate proteome and transcriptome profiles, enabling study of drug resistance and mode of action. The functional association network was constructed by Bayesian logistic regression, providing a framework for identification of antimicrobial peptide (ranalexin) response modules from S. aureus MRSA-252 transcriptome and proteome profiling. These signatures of ranalexin treatment revealed multiple killing mechanisms, including cell wall activity. Cell wall effects were supported by gene disruption and osmotic fragility experiments. Furthermore, twenty-two novel virulence factors were inferred, while the VraRS two-component system and PhoU-mediated persister formation were implicated in MRSA tolerance to cationic antimicrobial peptides. This work demonstrates a powerful integrative approach to study drug resistance and mode of action. Our findings are informative to the development of novel therapeutic strategies against Staphylococcus aureus and particularly MRSA.
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影响因子：
14.9
作者：
Barker, WC;Garavelli, JS;Wu, C
通讯作者：
Wu, C
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.8
作者：
Belcheva, Antoaneta;Golemi-Kotra, Dasantila
通讯作者：
Golemi-Kotra, Dasantila
影响因子：
3.6
作者：
Forsyth, RA;Haselbeck, RJ;Zyskind, JW
通讯作者：
Zyskind, JW
影响因子：
4.8
作者：
Downer, R;Roche, F;Foster, TJ
通讯作者：
Foster, TJ