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    • Here we hypothesized that abscesses represent a

    2018-11-05

    Here we hypothesized that abscesses represent a distinct stress-triggered growth state that make them both resistant to treatment and able to cause pathology. In particular, we have considered the involvement of the universal stringent stress response. The stringent response is a conserved stress response employed by various bacteria to respond to and cope with conditions of amino-acid starvation, carbon-source, fatty acid, oxygen or iron limitation, heat shock, antimicrobial challenge, and/or other environmental stressors (Crosse et al., 2000; Potrykus and Cashel, 2008). In most bacteria, the stringent response is signaled by the secondary-messenger guanosine tetraphosphate (ppGpp), which serves as a pleiotropic transcriptional regulator by binding to RNA polymerase (Dalebroux and Swanson, 2012). This leads to the repression of resource-consuming processes (translation, lipid, and cell wall biosynthesis, and to some extent replication and transcription) and diverts resources toward biosynthesis (amino Adriamycin HCl biosynthesis and transport, glycolysis) and diverse stress genes to promote survival (Potrykus and Cashel, 2008; Srivatsan and Wang, 2008; Wolz et al., 2010). Cationic amphipathic peptides are an evolutionarily conserved, multifunctional component of the innate immune system. They are known to have immunomodulatory, direct antimicrobial, and/or anti-biofilm activity (Hancock and Sahl, 2006). Importantly, a distinct subset of cationic peptides have demonstrated broad-spectrum efficacy in targeting recalcitrant biofilm infections by targeting the stringent stress response (de la Fuente-Núñez et al., 2014; de la Fuente-Núñez et al., 2015; Pletzer and Hancock, 2016). Biofilms are a distinct growth state of bacteria on surfaces whereby the bacteria form structured aggregates that are adaptively multi-antibiotic resistant (de la Fuente-Núñez et al., 2014; de la Fuente-Núñez et al., 2015; Overhage et al., 2008). The stringent response and biofilm formation are tightly interconnected processes since ppGpp is required for biofilm initiation and maintenance, such that bacterial mutants defective in the stringent response do not form biofilms (Aberg et al., 2006; de la Fuente-Núñez et al., 2014; He et al., 2012). In S. aureus, upon amino acid starvation, ppGpp (and its precursor pppGpp) production is mediated by the bi-functional synthase/hydrolase enzyme RSH (a RelA/SpoT homolog) (Geiger et al., 2012). The ppGpp regulon is very complex (Vercruysse et al., 2011). For example, in Escherichia coli, ppGpp mediates the induction of other stress regulators within the universal stress protein (USP) family (Kvint et al., 2003). Likewise, in S. aureus, a homolog, the universal stress protein (designated Usp2) was recently identified and shown to be necessary for persistence under amino acid starvation (Attia et al., 2013) and is positively regulated by ppGpp (Geiger et al., 2012). Despite these findings, the importance of these stringent response regulators in S. aureus pathogenesis remains an understudied topic. Here we have demonstrated a contribution of the stringent response to S. aureus cutaneous abscess formation (as judged by lesion formation and other altered pathology findings), but not local bacterial growth, and demonstrated that it can be targeted pharmacologically with a peptide. Furthermore, the same pharmacological targeting worked with P. aeruginosa infections in a cutaneous abscess model.
    Materials and Methods
    Results
    Discussion Bacteria are highly adaptive, dynamic organisms that use a variety of sensor systems to monitor and adapt to environmental conditions (Potrykus and Cashel, 2008). Here we showed that stringent stress adaption is a critical determinant of S. aureus cutaneous abscess lesion formation. The stringent response has been shown to mediate tolerance of S. aureus to cell wall-active antibiotics (Geiger et al., 2014) and we propose that this adaptation is in part responsible for the limited success of conventional antibiotics against bacteria in abscesses. Specifically, our data showed that mutants deficient in either of the two important stringent response mediators (RSH or Usp2), were impaired in lesion formation. Previous studies were somewhat ambiguous since although an rshsyn mutant formed fewer kidney abscesses in a murine renal abscess model (Geiger et al., 2010), this observation was proposed to reflect the lower viability (recovery of bacteria) of the rshsyn mutant compared to the wild type in the kidneys. In contrast, in the cutaneous abscess model, the very substantial attenuation of abscess lesion formation by the rshsyn mutant occurred despite similar levels of bacteria as the wild type, demonstrating a direct contribution of the stringent response. Consistent with this observation, by targeting the stringent response, DJK-5 was able to suppress tissue injury. Despite the major physiological differences in bacterial abscess and biofilm formation, our studies have revealed a strong mechanistic connection that can be exploited with antibiofilm peptides.