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    • In accordance with these observations we

    2018-11-14

    In accordance with these observations, we demonstrated the importance of a newly-identified stress response regulator, Usp2, both in Staphylococcal abscess lesion formation, albeit to a lesser extent than for the rshsyn mutant, and in biofilm formation. This correlates with recent studies that demonstrated the importance of Usp2 in responding to amino hoechst 33342 starvation (Attia et al., 2013). Biofilm formation is a survival strategy for bacteria to adapt to hostile environments and although bacteria in abscesses are largely considered to be loosely associated in pus, recent evidence suggests that bacteria isolated from deep tissue abscesses are embedded in biofilm-like matrices (May et al., 2014). Of great importance, recurring abscesses and biofilms are similarly recalcitrant to antibiotic therapy (Davies, 2003; Stearne et al., 2001). As such, cationic peptides that display antibiofilm activity, can target multidrug resistant bacteria and are synergistic with conventional antibiotics (de la Fuente-Núñez et al., 2014; de la Fuente-Núñez et al., 2015), represent excellent candidates for the adjunctive treatment of recalcitrant cutaneous abscesses. Our previous studies indicated that DJK-5, a small cationic peptide comprising of D-amino acids, possessed potent antibiofilm activity against a variety of multi-drug resistant Gram-negative species (de la Fuente-Núñez et al., 2015). Furthermore, DJK-5 targets the stress response alarmone ppGpp and enhances survival in two invertebrate P. aeruginosa biofilm infection models (de la Fuente-Núñez et al., 2015). Here we demonstrated that DJK-5 could suppress S. aureus and P. aeruginosa cutaneous injury in mice, despite the very different physiological states of biofilm and abscess infections. Also, the bacterial load recovered after use of the peptide employed at 3mg/kg IP, was similar to that for the commonly used antibiotic clindamycin at 75mg/kg (data not shown), highlighting its potential as an improved anti-abscess strategy. The stringent response triggers a complex cascade of transcriptional events to counteract environmental stresses. Given that high bacterial loads were still recovered from DJK-5-treated mice (Fig. 2d and 3b), we considered that the peptide might be suppressing a toxin and indeed demonstrated here that it suppressed the production of the major cutaneous PSM toxins of S. aureus. PSMs are positively regulated by the stringent response (Geiger et al., 2012) and consistent with this, our studies indicated that DJK-5 suppressed PSMα production, likely through stringent response impairment. PSMs recruit, activate and subsequently lyse neutrophils, the key effectors and first responders against bacterial infections (Berube et al., 2014). Previous studies have shown that upon uptake of S. aureus in neutrophils, the stringent response is elicited resulting in increased PSM synthesis, which contributes to survival after phagocytosis by mediating neutrophil lysis (Geiger et al., 2012). Thus by suppressing PSM production, DJK-5 could potentially reduce local tissue damage as well as impede a major immune evasion method employed by S. aureus. Given the 10-fold effect on bacterial load, we also considered the potential importance of effects on quorum sensing. Phenol soluble modulins are under the control of the accessory gene regulator (agr) quorum sensing pathway as well as the stringent response. However, studies have shown that production of phenol soluble modulins (especially the virulent α-type which are dysregulated by DJK-5), can be produced in an agr-independent manner (Wang et al., 2007). In fact, during the stringent response, RSH-independent induction of phenol soluble modulins, is not mediated by increased agr expression (Geiger et al., 2012), confirming a limited correlation between quorum sensing and phenol soluble modulin production under stringent conditions. In conclusion, we have uncovered mechanisms driving bacterial abscess lesion formation and provide a therapeutic approach to minimize the severity of skin infections by both Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa.