We have additionally observed a peculiar phenotype in S. aureus suggestive of a selective advantage afforded by the ACME cassette. Polyamines, including spermine, spermidine, and putrescine, are a group of polycationic compounds Akt inhibitor reportedly synthesized from l-arginine by all living organisms. Not only does S. aureus lack the ability to synthesize polyamines de novo, but spermine and spermidine are bactericidal to this organism at levels found within mammalian tissue (Baze et al., 1985; Joshi et al., 2011). Polyamine-sensitivity was apparent in all tested strains except those

belonging to USA300, and in these isolates, polyamine resistance was dependent on speG encoding a spermine/spermidine aceytltrasferase harbored on ACME. Could speG provide USA300 with a selective advantage by nullifying the staphylocidal effects of host polyamines? While no direct measure of host polyamine levels during S. aureus infections have been reported, several indirect lines of evidence may suggest that polyamines do affect the outcome of staphylococcal disease and/or colonization. Upon wounding, the host response in the skin is proinflammatory and dominated by cytokines such as IL-1, INF-γ, and TNF-α (Mahdavian Delavary et al., 2011). The

resulting inflammation is mediated, among other effectors, by the production of reactive oxygen and nitrogen Pifithrin-�� chemical structure species, the latter of which, nitric oxide (NO·) is synthesized from l-arginine by the inducible NO-synthase (iNOS, Fig. 2). This enzyme competes for available l-arginine with host enzymes such as Arginase-1 (Fig. 2) as well as with arginine-auxotrophic S. aureus (Emmett & Kloos, 1979). Once tissue damage signals resulting from the primary inflammation outweigh pathogen-associated signals, the host response shifts away from proinflammatory

mediators and initiates the profibrotic response (Mahdavian Delavary et al., 2011). This phase is dependent on the production of TH2-like anti-inflammatory cytokines such as IL-4, IL-10, IL-13, and TGFβ and results in induction 2-hydroxyphytanoyl-CoA lyase of host fibrotic response involving Arginase-1 expression. At this stage, the l-ornithine produced by Arginase-1 can be converted to staphylocidal polyamines that will additionally promote fibroblast proliferation, collagen deposition, and inhibition of inflammation (e.g. blocking iNOS translation) (Maeno et al., 1990). It therefore may be during this TH2-dominant fibrotic phase that host polyamines exert their effects on invading S. aureus thereby selecting for ACME-encoded SpeG. Indeed, inhibiting IL-4 signaling in mice increased organism burdens during S. aureus sepsis, while INF-γ−/− mice (lacking robust inflammatory wound response) survived better than WT mice (Sasaki et al., 2000). Thus, TH2-dependent signaling, as opposed to an inflammatory TH1 response, proved critical to the host’s ability to control S. aureus infections. Recently, protection against chronic implant infections was also highly dependent on an effective TH2/Treg response (Prabhakara et al.