Novel engineered #peptides of a #phage lysin as effective #antimicrobials against multidrug #resistant #Acinetobacter baumannii (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Novel engineered peptides of a phage lysin as effective antimicrobials against multidrug resistant Acinetobacter baumannii [      ]

Mya Thandar 1, Rolf Lood 1, Benjamin Y. Winer 1, Douglas R. Deutsch 1, Chad W. Euler 1 and Vincent A. Fischetti 1#

Author Affiliations: 1Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA

 

ABSTRACT

Acinetobacter baumannii is a Gram-negative bacterial pathogen responsible for a range of nosocomial infections. The recent rise and spread of multidrug resistant A. baumannii clones has fueled a search for alternative therapies, including bacteriophage endolysins with potent antibacterial activities. A common feature of these lysins is the presence of a highly positively charged C-terminal domain with a likely role in promoting outer membrane penetration. In the current study, we show that the C-terminal amino acid 108-138 of phage lysin PlyF307, named P307, alone was sufficient to kill A. baumannii (>3-logs). Furthermore, P307 could be engineered for improved activity, the most active derivative being P307SQ-8C (>5-log kill). Both P307 and P307SQ-8C showed high in vitro activity against A. baumannii in biofilms. Moreover, P307SQ-8C exhibited MICs comparable to levofloxacin and ceftazidime and acted synergistically with polymyxin B. While the peptides were shown to kill by disrupting the bacterial cytoplasmic membrane, they did not lyse human red blood cells or B cells; however, serum was found to be inhibitory to lytic activity. In a murine model of A. baumannii skin infection, P307SQ-8C reduced the bacterial burden by ∼2-logs in 2 h. This study demonstrates the prospect of using peptide derivatives from bacteriophage lysins to treat topical infections and remove biofilms caused by Gram-negative pathogens.

 

FOOTNOTES

#Corresponding author: Vincent A. Fischetti, vaf@rockefeller.edu

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Keywords: Research; Abstracts; Antibiotics; Drugs Resistance; Acinetobacter Baumannii; Bacteriophages.

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The recombinant #bacteriophage endolysin HY-133 exhibits in vitro activity against different African clonal #lineages of the S. aureus complex including S. schweitzeri (AAC, abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

The recombinant bacteriophage endolysin HY-133 exhibits in vitro activity against different African clonal lineages of the Staphylococcus aureus complex including Staphylococcus schweitzeri [      ]

Evgeny A. Idelevich 1, Frieder Schaumburg 1, Dennis Knaack 1, Anna S. Scherzinger 2, Wolfgang Mutter 2, Georg Peters 1, Andreas Peschel 3,4 and Karsten Becker 1#

Author Affiliations: 1Institute of Medical Microbiology, University Hospital Münster, Münster, Germany 2Hyglos GmbH, Bernried, Germany 3Interfaculty Institute of Microbiology and Infection Medicine, Infection Biology Department, University of Tübingen, Tübingen, Germany 4German Center for Infection Research (DZIF), Partner Site Tübingen, Tübingen, Germany.

 

ABSTRACT

HY-133 is a recombinant bacteriophage endolysin with bactericidal activity against Staphylococcus aureus. Here, HY-133 showed in vitro activity against major African methicillin-susceptible and methicillin-resistant S. aureus lineages, ceftaroline/ceftobiprole- and borderline oxacillin-resistant isolates. HY-133 was also active against Staphylococcus schweitzeri, a recently described species of S. aureus complex. The activity of HY-133 on the tested isolates (MIC50 0.25 μg/ml, MIC90 0.5 μg/ml, range 0.125-0.5 μg/ml) was independent of the species and strain background or antibiotic resistance.

FOOTNOTES

#Address correspondence to Karsten Becker, kbecker@uni-muenster.de

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Keywords: Research; Abstracts; Bacteriophages; S. Aureus.

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#Bacteriophage can prevent #encrustation and #blockage of #urinary #catheters by #Proteus mirabilis (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Bacteriophage can prevent encrustation and blockage of urinary catheters by Proteus mirabilis [      ]

Jonathan Nzakizwanayo a, Aurélie Hanin b, Diana R. Alves a,c,d, Benjamin McCutcheon a, Cinzia Dedi a, Jonathan Salvage a, Karen Knox e, Bruce Stewart e, Anthony Metcalfe a,c, Jason Clark f, Brendan Gilmore g, Cormac M. C. Gahan b, Toby A. Jenkins h and Brian V. Jones a,d#

Author Affiliations: aSchool of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, East Sussex, United Kingdom. bAlimentary Pharmabiotic Centre and School of Microbiology, University College Cork, Ireland. cBlond McIndoe Research Foundation, Queen Victoria Hospital, Holtye Road, East Grinstead, United Kingdom. dQueen Victoria Hospital NHS Foundation Trust, Holtye Road, East Grinstead, United Kingdom. eEast Surrey Hospital, Surrey and Sussex NHS Healthcare Trust, Redhill, Surrey, United Kingdom. fNovolytics Ltd, Daresbury Science and Innovation Campus, Warrington, United Kingdom. gSchool of Pharmacy, Queens University Belfast, Belfast, United Kingdom. hDepartment of Chemistry, University of Bath, Bath, United Kingdom.

 

ABSTRACT

Proteus mirabilis forms dense crystalline biofilms on catheter surfaces that occlude urine flow leading to serious clinical complications in long-term catheterised patients, but there are presently no truly effective approaches to control catheter blockage by this organism. This study evaluated the potential for bacteriophage therapy to control P. mirabilis infection and prevent catheter blockage. Representative in vitro models of the catheterised urinary tract, simulating a complete closed drainage system as used in clinical practice, were employed to evaluate the performance of phage therapy in preventing blockage. Models mimicking either an established infection, or early colonisation of the catheterised urinary tract, were treated with a single dose of a 3 phage cocktail, and the impact on time taken for catheters to block, as well as levels of crystalline biofilm formation, were measured. In models of established infection phage treatment significantly increased time taken for catheters to block (∼3-fold) compared to untreated controls. However, in models simulating early stage infection phage treatment eradicated P. mirabilis and prevented blockage entirely. Analysis of catheters from models of established infection, 10 hours after phage application, demonstrated that phage significantly reduced crystalline biofilm formation, but did not significantly reduce the level of planktonic cells in the residual “bladder” urine. Taken together, these results show that bacteriophage constitute a promising strategy for the prevention of catheter blockage, but that methods to deliver phage in sufficient numbers and within a key therapeutic window (early infection) will also be important to the successful application of phage to this problem.

 

FOOTNOTES

#Corresponding Author: Brian V. Jones, e-mail: b.v.jones@brighton.ac.uk

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Keywords: Research; Abstracts; Proteus Mirabilis; Bacteriophages.

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Better together: #bacteriophage combinations significantly reduce #Clostridium difficile #growth in vitro and proliferation in vivo (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Better together: bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo [      ]

Janet Y. Nale a, Janice Spencer b, Katherine R. Hargreaves a, Anthony M. Buckley b, Przemysław Trzepiński a,  Gillian R. Douce b# and Martha R. J. Clokie a#

Author Affiliations: aDepartment of Infection, Immunity and Inflammation, University of Leicester, Leicester, England, UK. bInstitute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, Sir Graham Davies Building, University Place, University of Glasgow, Scotland, UK

 

ABSTRACT

Microbiome dysbiosis caused by antibiotic treatment has been associated with both the susceptibility and relapsing of Clostridium difficile infection (CDI). Bacteriophage (phage) therapy offers target specificity and dose amplification in situ, but few studies have focused on their use in CDI treatment. This mainly reflects the lack of strictly virulent phages that target this pathogen. Whilst it is widely accepted that temperate phages are unsuitable for therapeutic purposes due to their transduction potential, analysis of seven C. difficile phages confirmed that this impact could be curtailed by the application of multiple phage types. Here, host range analysis of six myoviruses and one siphovirus was conducted on 80 strains representing 21 major epidemic and clinically severe ribotypes. The phages had complementary coverage; lysing 18 and 62 of the ribotypes and strains tested respectively. Single-phage treatments of ribotypes 076, 014/020 and 027 strains showed an initial reduction in bacterial load followed by emergence of phage-resistant colonies. However, these colonies remained susceptible to phage infection with an unrelated phage. In contrast, specific phage combinations caused complete lysis of C. difficile in vitro and prevented the appearance of resistant/lysogenic clones. Using a hamster model, oral delivery of optimized phage combinations resulted in reduced C. difficile colonization 36 h post-infection. Interestingly, free phages were recovered from the bowel at this time. In a challenge model of the disease, phage treatment delayed the onset of symptoms by 33 h compared to untreated animals. These data demonstrate the therapeutic potential of phage combinations to treat CDI.

 

FOOTNOTES

#Address correspondence to: M. R. J. Clokie, mrjc1@le.ac.uk and G. R. Douce. Gillian.Douce@glasgow.ac.uk

Copyright © 2015 Nale et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 International license.

Keywords: Research; Abstracts; Antibiotics; Drugs Resistance; Clostridium Difficile; Bacteriophages.

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