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

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.Methicillin Resistant Staphylococcus aureus (MRSA) is a major cause of morbidity and mortality [1-4]. Indeed, rates of MRSA infections have risen significantly in recent years [3,5]. Strains that are resistant to existing treatments continue to emerge and community-associated MRSA is a major global problem [3,4,6-10]. Therefore, the development of novel prevention and treatment strategies is a pressing concern.Antimicrobial peptides (AMPs) are a potential source of novel antibiotics that may be developed to combat resistant bacteria such as MRSA [11]. AMPs are produced by virtually all living creatures as part of their innate defences and more than 880 have been described [12]. Ranalexin is a cationic 20 amino acid peptide, first isolated from the American bullfrog, Rana catesbeiana, and has a single intramolecular disulphide bond to form a heptapeptide ring at the carboxyl terminus [13]. Ranalexin has potent activity against Gram-positive bacteria in vitro, particularly Staphylococcus aureus [14]. Therefore, ranalexin offers therapeutic potential against staphylococcal infections, including MRSA.Understandi