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      Antibacterial activity and therapeutic efficacy of Fl-P RP RP L-5, a cationic amphiphilic polyproline helix, in a mouse model of staphylococcal skin infection


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          The antibacterial activities and therapeutic efficacy of the cationic, unnatural proline-rich peptide Fl-P RP RP L-5 were evaluated against multidrug-resistant Staphylococcus aureus in a mouse model of skin infection. Fl-P RP RP L-5 showed potent activity against all clinical isolates of S. aureus tested, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA, respectively). Fl-P RP RP L-5 was also superior in clearing established in vitro biofilms of S. aureus and Staphylococcus epidermidis, compared with the established antimicrobials mupirocin and vancomycin. Additionally, topical treatment of an MRSA-infected wound with Fl-P RP RP L-5 enhanced wound closure and significantly reduced bacterial load. Finally, 0.5% Fl-P RP RP L-5 significantly reduced the levels of the inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) in wounds induced by MRSA skin infection. In conclusion, the results of this study suggest the potential application of Fl-P RP RP L-5 in the treatment of staphylococcal skin infections.

          Most cited references19

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          Targeting inflammation in the treatment of type 2 diabetes: time to start.

          The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.
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            Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections.

            Studies have shown that community-acquired methicillin-resistant Staphylococcus aureus (MRSA) causes S. aureus skin and soft-tissue infection in selected populations. To determine the proportion of infections caused by community-acquired MRSA, the clinical characteristics associated with community-acquired MRSA, and the molecular epidemiology of community-acquired MRSA among persons with community-onset S. aureus skin and soft-tissue infection. Active, prospective laboratory surveillance to identify S. aureus recovered from skin and soft-tissue sources. 1000-bed urban hospital and its affiliated outpatient clinics in Atlanta, Georgia. 384 persons with microbiologically confirmed community-onset S. aureus skin and soft-tissue infection. Proportion of infections caused by and clinical factors associated with community-acquired MRSA among persons with community-onset S. aureus skin and soft-tissue infection. Pulsed-field gel electrophoresis and antimicrobial susceptibility patterns were used to epidemiologically classify community-onset S. aureus infections. Community-acquired MRSA was defined by MRSA isolates that either demonstrated a USA 300 or USA 400 pulsed-field type or had a susceptibility pattern showing resistance only to beta-lactams and erythromycin (for isolates not available for pulsed-field gel electrophoresis). Community-onset skin and soft-tissue infection due to S. aureus was identified in 389 episodes, with MRSA accounting for 72% (279 of 389 episodes). Among all S. aureus isolates, 63% (244 of 389 isolates) were community-acquired MRSA. Among MRSA isolates, 87% (244 of 279 isolates) were community-acquired MRSA. When analysis was restricted only to MRSA isolates that were available for pulsed-field gel electrophoresis, 91% (159 of 175 isolates) had a pulsed-field type consistent with community-acquired MRSA; of these, 99% (157 of 159 isolates) were the MRSA USA 300 clone. Factors independently associated with community-acquired MRSA infection were black race (prevalence ratio, 1.53 [95% CI, 1.16 to 2.02]), female sex (prevalence ratio, 1.16 [CI, 1.02 to 1.32]), and hospitalization within the previous 12 months (prevalence ratio, 0.80 [CI, 0.66 to 0.97]). Inadequate initial antibiotic therapy was statistically significantly more common among those with community-acquired MRSA (65%) than among those with methicillin-susceptible S. aureus skin and soft-tissue infection (1%). Some MRSA isolates were not available for molecular typing. The community-acquired MRSA USA 300 clone was the predominant cause of community-onset S. aureus skin and soft-tissue infection. Empirical use of agents active against community-acquired MRSA is warranted for patients presenting with serious skin and soft-tissue infections.
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              Targeting methicillin-resistant Staphylococcus aureus with short salt-resistant synthetic peptides.

              The seriousness of microbial resistance combined with the lack of new antimicrobials has increased interest in the development of antimicrobial peptides (AMPs) as novel therapeutics. In this study, we evaluated the antimicrobial activities of two short synthetic peptides, namely, RRIKA and RR. These peptides exhibited potent antimicrobial activity against Staphylococcus aureus, and their antimicrobial effects were significantly enhanced by addition of three amino acids in the C terminus, which consequently increased the amphipathicity, hydrophobicity, and net charge. Moreover, RRIKA and RR demonstrated a significant and rapid bactericidal effect against clinical and drug-resistant Staphylococcus isolates, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA), linezolid-resistant S. aureus, and methicillin-resistant Staphylococcus epidermidis. In contrast to many natural AMPs, RRIKA and RR retained their activity in the presence of physiological concentrations of NaCl and MgCl2. Both RRIKA and RR enhanced the killing of lysostaphin more than 1,000-fold and eradicated MRSA and VRSA isolates within 20 min. Furthermore, the peptides presented were superior in reducing adherent biofilms of S. aureus and S. epidermidis compared to results with conventional antibiotics. Our findings indicate that the staphylocidal effects of our peptides were through permeabilization of the bacterial membrane, leading to leakage of cytoplasmic contents and cell death. Furthermore, peptides were not toxic to HeLa cells at 4- to 8-fold their antimicrobial concentrations. The potent and salt-insensitive antimicrobial activities of these peptides present an attractive therapeutic candidate for treatment of multidrug-resistant S. aureus infections. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                22 October 2015
                : 9
                : 5749-5754
                [1 ]Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA
                [2 ]Department of Chemistry, Purdue University, West Lafayette, IN, USA
                Author notes
                Correspondence: Mohamed N Seleem, Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, 625 Harrison St, West Lafayette, IN, 47907, USA, Tel +1 765 494 0763, Fax +1 765 496 2627, Email mseleem@ 123456purdue.edu
                © 2015 Thangamani et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine
                antimicrobial peptides,staphylococcus aureus,biofilms,anti-inflammatory,skin infection


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