title: Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus.
abstract: 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.
authors.affiliation: Biomedical Systems Analysis, MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK. ian.overton@hgu.mrc.ac.uk
authors.forename: Ian M
authors.initials: IM
authors.lastname: Overton
authors.forename: Shirley
authors.initials: S
authors.lastname: Graham
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Gould
authors.forename: Jason
authors.initials: J
authors.lastname: Hinds
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Botting
authors.forename: Sally
authors.initials: S
authors.lastname: Shirran
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Barton
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Coote
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry; D001499:Bayes Theorem; D002473:Cell Wall / Q000378:metabolism; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D016106:Methicillin Resistance / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000235:genetics*; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000494:pharmacology; D012044:Regression Analysis; D013211:Staphylococcus aureus / Q000235:genetics; D049490:Systems Biology / Q000379:methods; D014774:Virulence; D037521:Virulence Factors
chemical_list: D000890:Anti-Infective Agents; D010456:Peptides, Cyclic; D037521:Virulence Factors; C086618:ranalexin