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Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus

Overton, IM; Graham, S; Gould, KA; Hinds, J; Botting, CH; Shirran, S; Barton, GJ; Coote, PJ (2011) Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus. BMC SYSTEMS BIOLOGY, 5 (68). ISSN 1752-0509
SGUL Authors: Gould, Katherine Ann Hinds, Jason

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Background: 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. Results: 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. Conclusions: 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.

Item Type: Article
Additional Information: 2011 Overton et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Anti-Infective Agents, Bayes Theorem, Cell Wall, Computational Biology, Gene Expression Profiling, Gene Expression Regulation, Bacterial, Humans, Methicillin Resistance, Methicillin-Resistant Staphylococcus aureus, Microbial Sensitivity Tests, Peptides, Cyclic, Regression Analysis, Staphylococcus aureus, Systems Biology, Virulence, Virulence Factors, Science & Technology, Life Sciences & Biomedicine, Mathematical & Computational Biology, MATHEMATICAL & COMPUTATIONAL BIOLOGY, PEPTIDE-SENSING SYSTEM, FALSE DISCOVERY RATE, CELL-WALL-DAMAGE, STAPHYLOCOCCUS-AUREUS, ANTIMICROBIAL PEPTIDES, 2-COMPONENT SYSTEM, ESCHERICHIA-COLI, BINDING PROTEIN, UNITED-STATES, EXPRESSION, Bioinformatics, Other Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: BMC SYSTEMS BIOLOGY
ISSN: 1752-0509
Related URLs:
12 May 2011Published
Web of Science ID: WOS:000292105100001
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