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      The novel antimicrobial peptide PXL150 in the local treatment of skin and soft tissue infections

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          Abstract

          Dramatic increase in bacterial resistance towards conventional antibiotics emphasises the importance to identify novel, more potent antimicrobial therapies. Antimicrobial peptides (AMPs) have emerged as a promising new group to be evaluated in therapeutic intervention of infectious diseases. Here we describe a novel AMP, PXL150, which demonstrates in vitro a broad spectrum microbicidal action against both Gram-positive and Gram-negative bacteria, including resistant strains. The potent microbicidal activity and broad antibacterial spectrum of PXL150 were not associated with any hemolytic activity. Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) failed to develop resistance towards PXL150 during continued selection pressure. PXL150 caused a rapid depolarisation of cytoplasmic membrane of S. aureus, and dissipating membrane potential is likely one mechanism for PXL150 to kill its target bacteria. Studies in human cell lines indicated that PXL150 has anti-inflammatory properties, which might be of additional benefit. PXL150 demonstrated pronounced anti-infectious effect in an in vivo model of full thickness wounds infected with MRSA in rats and in an ex vivo model of pig skin infected with S. aureus. Subcutaneous or topical application of the peptide in rats did not lead to any adverse reactions. In conclusion, PXL150 may constitute a new therapeutic alternative for local treatment of infections, and further studies are warranted to evaluate the applicability of this AMP in clinical settings.

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          The online version of this article (doi:10.1007/s00253-012-4439-8) contains supplementary material, which is available to authorized users.

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          Most cited references22

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          The relationship between peptide structure and antibacterial activity.

          Cationic antimicrobial peptides are a class of small, positively charged peptides known for their broad-spectrum antimicrobial activity. These peptides have also been shown to possess anti-viral and anti-cancer activity and, most recently, the ability to modulate the innate immune response. To date, a large number of antimicrobial peptides have been chemically characterized, however, few high-resolution structures are available. Structure-activity studies of these peptides reveal two main requirements for antimicrobial activity, (1) a cationic charge and (2) an induced amphipathic conformation. In addition to peptide conformation, the role of membrane lipid composition, specifically non-bilayer lipids, on peptide activity will also be discussed.
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            Multifunctional cationic host defence peptides and their clinical applications.

            With the rapid rise in the emergence of bacterial strains resistant to multiple classes of antimicrobial agents, there is an urgent need to develop novel antimicrobial therapies to combat these pathogens. Cationic host defence peptides (HDPs) and synthetic derivatives termed innate defence regulators (IDRs) represent a promising alternative approach in the treatment of microbial-related diseases. Cationic HDPs (also termed antimicrobial peptides) have emerged from their origins as nature's antibiotics and are widely distributed in organisms from insects to plants to mammals and non-mammalian vertebrates. Although their original and primary function was proposed to be direct antimicrobial activity against bacteria, fungi, parasites and/or viruses, cationic HDPs are becoming increasingly recognized as multifunctional mediators, with both antimicrobial activity and diverse immunomodulatory properties. Here we provide an overview of the antimicrobial and immunomodulatory activities of cationic HDPs, and discuss their potential application as beneficial therapeutics in overcoming infectious diseases.
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              National trends in ambulatory visits and antibiotic prescribing for skin and soft-tissue infections.

              Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a common cause of skin and soft-tissue infections (SSTIs) in the United States. It is unknown whether this development has affected the national rate of visits to primary care practices and emergency departments (EDs) and whether changes in antibiotic prescribing have occurred. We examined visits by patients with SSTIs to physician offices, hospital outpatient departments, and EDs using the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey from 1997 to 2005. We estimated annual visit rates for all SSTIs and a subset classified as abscess/cellulitis. For abscess/cellulitis visits, we examined trends in characteristics of patients and clinical settings and in antibiotic prescribing. Overall rate of visits for SSTIs increased from 32.1 to 48.1 visits per 1000 population (50%; P = .003 for trend), reaching 14.2 million by 2005. More than 95% of this change was attributable to visits for abscess/cellulitis, which increased from 17.3 to 32.5 visits per 1000 population (88% increase; P < .001 for trend). The largest relative increases occurred in EDs (especially in high safety-net-status EDs and in the South), among black patients, and among patients younger than 18 years. Use of antibiotics recommended for CA-MRSA increased from 7% to 28% of visits (P < .001) during the study period. Independent predictors of treatment with these antibiotics included being younger than 45 years, living in the South, and an ED setting. The incidence of SSTIs has rapidly increased nationwide in the CA-MRSA era and appears to disproportionately affect certain populations. Although physicians are beginning to modify antibiotic prescribing practices, opportunities for improvement exist, targeting physicians caring for patients who are at high risk.
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                Author and article information

                Contributors
                +46-31-7622902 , margit.mahlapuu@pergamum.com
                Journal
                Appl Microbiol Biotechnol
                Appl. Microbiol. Biotechnol
                Applied Microbiology and Biotechnology
                Springer-Verlag (Berlin/Heidelberg )
                0175-7598
                1432-0614
                4 October 2012
                4 October 2012
                April 2013
                : 97
                : 7
                : 3085-3096
                Affiliations
                Pergamum AB, Arvid Wallgrens Backe 20, 413 46 Gothenburg, Sweden
                Article
                4439
                10.1007/s00253-012-4439-8
                3602619
                23053090
                4298f9f9-8c10-4495-be21-e70e6fb198b5
                © The Author(s) 2012
                History
                : 11 July 2012
                : 10 September 2012
                : 11 September 2012
                Categories
                Applied Microbial and Cell Physiology
                Custom metadata
                © Springer-Verlag 2013

                Biotechnology
                antibiotic resistance,antimicrobial peptide,mrsa,staphylococcus aureus,wound infection

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