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

Ian M. Overton, Shirley Graham, Katherine A. Gould, Jason Hinds, Catherine H. Botting, Sally Shirran, Geoffrey J. Barton, Peter J. Coote

    Research output: Contribution to journalArticle

    22 Citations (Scopus)

    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.

    Original languageEnglish
    Article number68
    Pages (from-to)-
    Number of pages16
    JournalBMC Systems Biology
    Volume5
    DOIs
    Publication statusPublished - 12 May 2011

    Keywords

    • PEPTIDE-SENSING SYSTEM
    • FALSE DISCOVERY RATE
    • CELL-WALL-DAMAGE
    • STAPHYLOCOCCUS-AUREUS
    • ANTIMICROBIAL PEPTIDES
    • 2-COMPONENT SYSTEM
    • ESCHERICHIA-COLI
    • BINDING PROTEIN
    • UNITED-STATES
    • EXPRESSION

    Cite this

    Overton, I. M., Graham, S., Gould, K. A., Hinds, J., Botting, C. H., Shirran, S., ... Coote, P. J. (2011). Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus. BMC Systems Biology, 5, -. [68]. https://doi.org/10.1186/1752-0509-5-68
    Overton, Ian M. ; Graham, Shirley ; Gould, Katherine A. ; Hinds, Jason ; Botting, Catherine H. ; Shirran, Sally ; Barton, Geoffrey J. ; Coote, Peter J. / Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus. In: BMC Systems Biology. 2011 ; Vol. 5. pp. -.
    @article{2d7aea9e334c4cc58728de0b6b360b56,
    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.",
    keywords = "PEPTIDE-SENSING SYSTEM, FALSE DISCOVERY RATE, CELL-WALL-DAMAGE, STAPHYLOCOCCUS-AUREUS, ANTIMICROBIAL PEPTIDES, 2-COMPONENT SYSTEM, ESCHERICHIA-COLI, BINDING PROTEIN, UNITED-STATES, EXPRESSION",
    author = "Overton, {Ian M.} and Shirley Graham and Gould, {Katherine A.} and Jason Hinds and Botting, {Catherine H.} and Sally Shirran and Barton, {Geoffrey J.} and Coote, {Peter J.}",
    year = "2011",
    month = "5",
    day = "12",
    doi = "10.1186/1752-0509-5-68",
    language = "English",
    volume = "5",
    pages = "--",
    journal = "BMC Systems Biology",
    issn = "1752-0509",
    publisher = "Springer Verlag",

    }

    Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus. / Overton, Ian M.; Graham, Shirley; Gould, Katherine A.; Hinds, Jason; Botting, Catherine H.; Shirran, Sally; Barton, Geoffrey J.; Coote, Peter J.

    In: BMC Systems Biology, Vol. 5, 68, 12.05.2011, p. -.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus

    AU - Overton, Ian M.

    AU - Graham, Shirley

    AU - Gould, Katherine A.

    AU - Hinds, Jason

    AU - Botting, Catherine H.

    AU - Shirran, Sally

    AU - Barton, Geoffrey J.

    AU - Coote, Peter J.

    PY - 2011/5/12

    Y1 - 2011/5/12

    N2 - 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.

    AB - 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.

    KW - PEPTIDE-SENSING SYSTEM

    KW - FALSE DISCOVERY RATE

    KW - CELL-WALL-DAMAGE

    KW - STAPHYLOCOCCUS-AUREUS

    KW - ANTIMICROBIAL PEPTIDES

    KW - 2-COMPONENT SYSTEM

    KW - ESCHERICHIA-COLI

    KW - BINDING PROTEIN

    KW - UNITED-STATES

    KW - EXPRESSION

    U2 - 10.1186/1752-0509-5-68

    DO - 10.1186/1752-0509-5-68

    M3 - Article

    C2 - 21569391

    VL - 5

    SP - -

    JO - BMC Systems Biology

    JF - BMC Systems Biology

    SN - 1752-0509

    M1 - 68

    ER -