Dataset Information

Therapeutic Potential of an Endolysin Derived from Kayvirus S25-3 for Staphylococcal Impetigo.

ABSTRACT: Impetigo is a contagious skin infection predominantly caused by Staphylococcus aureus. Decontamination of S. aureus from the skin is becoming more difficult because of the emergence of antibiotic-resistant strains. Bacteriophage endolysins are less likely to invoke resistance and can eliminate the target bacteria without disturbance of the normal microflora. In this study, we investigated the therapeutic potential of a recombinant endolysin derived from kayvirus S25-3 against staphylococcal impetigo in an experimental setting. First, the recombinant S25-3 endolysin required an incubation period of over 15 minutes to exhibit efficient bactericidal effects against S. aureus. Second, topical application of the recombinant S25-3 endolysin decreased the number of intraepidermal staphylococci and the size of pustules in an experimental mouse model of impetigo. Third, treatment with the recombinant S25-3 endolysin increased the diversity of the skin microbiota in the same mice. Finally, we revealed the genus-specific bacteriolytic effect of recombinant S25-3 endolysin against staphylococci, particularly S. aureus, among human skin commensal bacteria. Therefore, topical treatment with recombinant S25-3 endolysin can be a promising disease management procedure for staphylococcal impetigo by efficient bacteriolysis of S. aureus while improving the cutaneous bacterial microflora.

SUBMITTER: Imanishi I

PROVIDER: S-EPMC6784202 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Therapeutic Potential of an Endolysin Derived from Kayvirus S25-3 for Staphylococcal Impetigo.

Imanishi Ichiro I Uchiyama Jumpei J Tsukui Toshihiro T Hisatsune Junzo J Ide Kaori K Matsuzaki Shigenobu S Sugai Motoyuki M Nishifuji Koji K

Viruses 20190822 9

Impetigo is a contagious skin infection predominantly caused by <i>Staphylococcus aureus</i>. Decontamination of <i>S. aureus</i> from the skin is becoming more difficult because of the emergence of antibiotic-resistant strains. Bacteriophage endolysins are less likely to invoke resistance and can eliminate the target bacteria without disturbance of the normal microflora. In this study, we investigated the therapeutic potential of a recombinant endolysin derived from kayvirus S25-3 against staph ...[more]

PMID: 31443379

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Project description:Previous studies have demonstrated that staphylococcal superantigen-like protein 7 (SSL7), a protein produced by Staphylococcus aureus, potently inhibits the formation of the complement membrane attack complex by binding to complement component 5 (C5). However, because of the predicted immunogenicity of SSL7 as a foreign protein in humans, its potential as a new complement inhibitor for treating complement-mediated diseases is uncertain. In this study, we found that administration of SSL7 significantly prevented complement-mediated hemolysis and reduced hemoglobinuria in a mouse model of complement-mediated intravascular hemolysis. Interestingly, although repetitive administrations of SSL7 elicited anti-SSL7 antibody production, administration of SSL7 at a dose of 2 ?g/mouse was still able to significantly attenuate complement-mediated intravascular hemolysis in vivo in the presence of the antibodies. In addition, even though anti-SSL7 antibodies were detectable in normal human donors, these antibodies did not significantly reduce the complement inhibitory activity of SSL7 in in vitro assays. Finally, inoculation of SSL7 in the anterior chamber of the eye suppressed the production of SSL7-reactive antibodies after repetitive SSL7 administration. These results suggest that SSL7 could be developed as an economical alternative to the existing C5-targeted drug, eculizumab, especially for controlling acute complement activation in catastrophic conditions such as drug-induced immune hemolytic anemia and ABO-incompatible erythrocyte transfusions. These data also suggest that approaches such as anterior chamber-associated immune deviation could be employed to establish an antigen-specific immune tolerance for long-term SSL7 administration. KEY MESSAGES:• SSL7 functions in the presence of anti-SSL7 antibodies both in vitro and in vivo. • SSL7 has the potential to be developed as a new and economical complement inhibitor for treating complement-mediated hemolysis.

Project description:The spread of antibiotic-resistant bacteria (ARB) in human and veterinary medicine is of global concern. Notably, the emergence of methicillin-resistant Staphylococcus pseudintermedius has become a serious problem. In this context, bacteriophages and their lytic enzymes, endolysins, have received considerable attention as therapeutics for infectious diseases in place of antibiotics. The aim of the present study was to investigate the antibiotic-resistance patterns of staphylococcal species isolated from canine skin at a primary care animal hospital in Tokyo, Japan and evaluate the lytic activity of the staphylococcal bacteriophage phiSA012 and its endolysin Lys-phiSA012 against isolated antibiotic-resistant staphylococcal strains. Forty clinical staphylococcal samples were isolated from infection sites of dogs (20 from skin and 20 from the external ear canal). Susceptibility to antimicrobial agents was determined by a disk diffusion method. The host range of phiSA012 was determined by using a spot test against staphylococcal isolates. Against staphylococcal isolates that showed resistance toward five classes or more of antimicrobials, the lytic activity of phiSA012 and Lys-phiSA012 was evaluated using a turbidity reduction assay. Twenty-three S. pseudintermedius, 16 Staphylococcus schleiferi, and 1 Staphylococcus intermedius were detected from canine skin and ear infections, and results revealed 43.5% methicillin resistance in S. pseudintermedius and 31.3% in S. schleiferi. In addition, the prevalence multidrug resistance (MDR) S. pseudintermedius was 65.2%. PhiSA012 could infect all staphylococcal isolates by spot testing, but showed little lytic activity by turbidity reduction assay against MDR S. pseudintermedius isolates. On the other hand, Lys-phiSA012 showed lytic activity and reduced significantly the number of staphylococcal colony-forming units. These results demonstrated that ARB issues underlying in small animal hospital and proposed substitutes for antibiotics. Lys-phiSA012 has broader lytic activity than phiSA012 against staphylococcal isolates; therefore, Lys-phiSA012 is a more potential candidate therapeutic agent for several staphylococcal infections including that of canine skin.

Project description:Kayviruses are polyvalent broad host range staphylococcal phages with a potential to combat staphylococcal infections. However, the implementation of rational phage therapy in medicine requires a thorough understanding of the interactions between bacteriophages and pathogens at omics level. To evaluate the effect of a phage used in therapy on its host bacterium, we performed differential transcriptomic analysis by RNA-Seq from bacteriophage K of genus Kayvirus infecting two Staphylococcus aureus strains, prophage-less strain SH1000 and quadruple lysogenic strain Newman. The temporal transcriptional profile of phage K was comparable in both strains except for a few loci encoding hypothetical proteins. Stranded sequencing revealed transcription of phage noncoding RNAs that may play a role in the regulation of phage and host gene expression. The transcriptional response of S. aureus to phage K infection resembles a general stress response with differential expression of genes involved in a DNA damage response. The host transcriptional changes involved upregulation of nucleotide, amino acid and energy synthesis and transporter genes and downregulation of host transcription factors. The interaction of phage K with variable genetic elements of the host showed slight upregulation of gene expression of prophage integrases and antirepressors. The virulence genes involved in adhesion and immune evasion were only marginally affected, making phage K suitable for therapy. IMPORTANCE Bacterium Staphylococcus aureus is a common human and veterinary pathogen that causes mild to life-threatening infections. As strains of S. aureus are becoming increasingly resistant to multiple antibiotics, the need to search for new therapeutics is urgent. A promising alternative to antibiotic treatment of staphylococcal infections is a phage therapy using lytic phages from the genus Kayvirus. Here, we present a comprehensive view on the phage-bacterium interactions on transcriptomic level that improves the knowledge of molecular mechanisms underlying the Kayvirus lytic action. The results will ensure safer usage of the phage therapeutics and may also serve as a basis for the development of new antibacterial strategies.

Project description:BACKGROUND:Impetigo is a common, superficial bacterial skin infection, which is most frequently encountered in children. There is no generally agreed standard therapy, and guidelines for treatment differ widely. Treatment options include many different oral and topical antibiotics as well as disinfectants. This is an updated version of the original review published in 2003. OBJECTIVES:To assess the effects of treatments for impetigo, including non-pharmacological interventions and 'waiting for natural resolution'. SEARCH METHODS:We updated our searches of the following databases to July 2010: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 2005), EMBASE (from 2007), and LILACS (from 1982). We also searched online trials registries for ongoing trials, and we handsearched the reference lists of new studies found in the updated search. SELECTION CRITERIA:Randomised controlled trials of treatments for non-bullous, bullous, primary, and secondary impetigo. DATA COLLECTION AND ANALYSIS:Two independent authors undertook all steps in data collection. We performed quality assessments and data collection in two separate stages. MAIN RESULTS:We included 57 trials in the first version of this review. For this update 1 of those trials was excluded and 12 new trials were added. The total number of included trials was, thus, 68, with 5578 participants, reporting on 50 different treatments, including placebo. Most trials were in primary impetigo or did not specify this.For many of the items that were assessed for risk of bias, most studies did not provide enough information. Fifteen studies reported blinding of participants and outcome assessors.Topical antibiotic treatment showed better cure rates than placebo (pooled risk ratio (RR) 2. 24, 95% confidence interval (CI) 1.61 to 3.13) in 6 studies with 575 participants. In 4 studies with 440 participants, there was no clear evidence that either of the most commonly studied topical antibiotics (mupirocin and fusidic acid) was more effective than the other (RR 1.03, 95% CI 0.95 to 1.11).In 10 studies with 581 participants, topical mupirocin was shown to be slightly superior to oral erythromycin (pooled RR 1.07, 95% CI 1.01 to 1.13). There were no significant differences in cure rates from treatment with topical versus other oral antibiotics. There were, however, differences in the outcome from treatment with different oral antibiotics: penicillin was inferior to erythromycin, in 2 studies with 79 participants (pooled RR 1.29, 95% CI 1.07 to 1.56), and cloxacillin, in 2 studies with 166 participants (pooled RR 1.59, 95% CI 1.21 to 2.08).There was a lack of evidence for the benefit of using disinfectant solutions. When 2 studies with 292 participants were pooled, topical antibiotics were significantly better than disinfecting treatments (RR 1.15, 95% CI 1.01 to 1.32).The reported number of side-effects was low, and most of these were mild. Side-effects were more common for oral antibiotic treatment compared to topical treatment. Gastrointestinal effects accounted for most of the difference.Worldwide, bacteria causing impetigo show growing resistance rates for commonly used antibiotics. For a newly developed topical treatment, retapamulin, no resistance has yet been reported. AUTHORS' CONCLUSIONS:There is good evidence that topical mupirocin and topical fusidic acid are equally, or more, effective than oral treatment. Due to the lack of studies in people with extensive impetigo, it is unclear if oral antibiotics are superior to topical antibiotics in this group. Fusidic acid and mupirocin are of similar efficacy. Penicillin was not as effective as most other antibiotics. There is a lack of evidence to support disinfection measures to manage impetigo.

Dataset Information

Therapeutic Potential of an Endolysin Derived from Kayvirus S25-3 for Staphylococcal Impetigo.

Publications

Therapeutic Potential of an Endolysin Derived from Kayvirus S25-3 for Staphylococcal Impetigo.

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