#Prophylaxis of Mycobacterium #tuberculosis H37Rv #Infection in a Preclinical Mouse Model via Inhalation of Nebulized #Bacteriophage D29 (Antimicrob Agents Chemother., abstract)

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

Prophylaxis of Mycobacterium tuberculosis H37Rv Infection in a Preclinical Mouse Model via Inhalation of Nebulized Bacteriophage D29

Nicholas B. Carrigy, Sasha E. Larsen, Valerie Reese, Tiffany Pecor, Melissa Harrison, Philip J. Kuehl, Graham F. Hatfull, Dominic Sauvageau, Susan L. Baldwin, Warren H. Finlay, Rhea N. Coler, Reinhard Vehring

DOI: 10.1128/AAC.00871-19

 

ABSTRACT

Globally, more people die annually from tuberculosis than from any other single infectious agent. Unfortunately, there is no commercially-available vaccine that is sufficiently effective at preventing acquisition of pulmonary tuberculosis in adults. In this study, pre-exposure prophylactic pulmonary delivery of active aerosolized anti-tuberculosis bacteriophage D29 was evaluated as an option for protection against Mycobacterium tuberculosis infection. An average bacteriophage concentration of approximately 1 PFU/alveolus was achieved in the lungs of mice using a nose-only inhalation device optimized with a dose simulation technique and adapted for use with a vibrating mesh nebulizer. Within 30 minutes of bacteriophage delivery, the mice received either a low dose (∼50-100 CFU), or an ultra-low dose (∼5-10 CFU), of M. tuberculosis H37Rv aerosol to the lungs. A prophylactic effect was observed with bacteriophage aerosol pre-treatment significantly decreasing M. tuberculosis burden in mouse lungs 24 hours and 3 weeks post-challenge (p < 0.05). These novel results indicate that a sufficient dose of nebulized mycobacteriophage aerosol to the lungs may be a valuable intervention to provide extra protection to health care professionals and other individuals at risk of exposure to M. tuberculosis.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Mycobacterium tuberculosis; Bacteriophages; Animal models.

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Therapeutic Effects of Intravitreously Administered #Bacteriophage in a Mouse Model of #Endophthalmitis Caused by #Vancomycin-Sensitive or -Resistant #Enterococcus faecalis (Antimicrob Agents Chemother., abstract)

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

Therapeutic Effects of Intravitreously Administered Bacteriophage in a Mouse Model of Endophthalmitis Caused by Vancomycin-Sensitive or -Resistant Enterococcus faecalis

Tatsuma Kishimoto, Waka Ishida, Ken Fukuda, Isana Nakajima, Takashi Suzuki, Jumpei Uchiyama, Shigenobu Matsuzaki, Daisuke Todokoro, Masanori Daibata, Atsuki Fukushima

DOI: 10.1128/AAC.01088-19

 

ABSTRACT

Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have now demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis. Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis–related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 colony forming units and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Vancomycin; Enterococcus faecalis; Endophthalmitis; Bacteriophages.

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Non-traditional #Antibacterial #Therapeutic #Options and #Challenges (Cell Host Microbe, abstract)

[Source: Cell, Host & Microbe, full page: (LINK). Abstract, edited.]

Non-traditional Antibacterial Therapeutic Options and Challenges

Ursula Theuretzbacher, Laura J.V. Piddock

DOI: https://doi.org/10.1016/j.chom.2019.06.004

 

Summary

The global challenges presented by drug-resistant bacterial infections have stimulated much activity in finding new treatments. This review summarizes the progress and setbacks of non-traditional approaches intent on circumventing bacterial drug resistance. These approaches include targeting virulence via toxin production and virulence factor secretion, impeding bacterial adhesion to host cells and biofilm formation, interrupting or inhibiting bacterial communication, and downregulating virulence. Other strategies include immune evasion, microbiome-modifying therapies, and the employment of phages as treatments or carriers. Finally, the prospects of nanoparticles, immunotherapy, antisense RNA, and drug-resistance-modulation approaches are discussed. The development of non-traditional treatments suffers similar challenges faced by developers of conventional antibiotics; however, most of these new strategies have additional and considerable hurdles before it can be shown that they are safe and efficacious for patient use. For the foreseeable future, it is likely that most of these treatments, if approved, will be used in combination with antibiotics.

Keywords: anti-virulence – quorum-sensing – microbiome – phage – nanoparticles – immunotherapy – antisense RNA – non-traditional antimicrobials

Keywords: Antibiotics; Drugs Resistance; Immunotherapy; Bacteriophages.

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#Phage #therapy of #pneumonia is not associated with an over stimulation of the #inflammatory response compared to #antibiotic treatment in mice (Antimicrob Agents Chemother., abstract)

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

Phage therapy of pneumonia is not associated with an over stimulation of the inflammatory response compared to antibiotic treatment in mice

Nicolas Dufour, Raphaëlle Delattre, Anne Chevallereau, Jean-Damien Ricard, Laurent Debarbieux

DOI: 10.1128/AAC.00379-19

 

ABSTRACT

Background.

Supported by years of clinical use in some countries and more recently by literature on experimental models as well as compassionate use in Europe and in USA, bacteriophage (phage) therapy is providing a solution for difficult to treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce.

Methods.

Murine acute pneumonia initiated by intranasal instillation of two pathogenic strains of Escherichia coli (536 and LM33) were treated by two specific bacteriophages (536_P1 and LM33_P1; intranasal) or antibiotics (Ceftriaxone, Cefoxitin, Imipenem-Cilastatin; intraperitoneal). Healthy mice also received phages alone. Severity of pulmonary edema, acute inflammatory cytokines (blood and lung homogenates), complete blood count, bacteria and bacteriophages counts were obtained at early (≤12h) and late (≥20h) time points.

Results.

Bacteriophage’s efficacy to decrease bacterial load was faster than antibiotics, but both displayed similar endpoints. Bacteriophage treatment was not associated with an over-inflammation but in contrast tended to lower inflammation and provided a faster correction of blood cell count abnormalities compared to antibiotics. In absence of bacterial infection, bacteriophage 536_P1 promoted a weak increase in the production of anti-viral cytokines (INF-γ and IL-12) and chemokines in the lungs, but not in the blood. However, such variations were no longer observed when bacteriophage 536_P1 was administered to treat infected animals.

Conclusions.

The rapid lysis of bacteria by bacteriophages in vivo does not increase the innate inflammatory response compared to an antibiotic treatment.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Bacteriophages; Pneumonia; Animal models.

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Specific and Selective #Bacteriophages in the Fight against #MDR #Acinetobacter baumannii (Virol Sin., abstract)

[Source: Virologica Sinica, full page: (LINK). Abstract, edited.]

Specific and Selective Bacteriophages in the Fight against Multidrug-resistant Acinetobacter baumannii

Authors: Natalia Bagińska, Anna Pichlak, Andrzej Górski, Ewa Jończyk-Matysiak

Review / First Online: 15 May 2019

 

Abstract

Acinetobacter baumannii causes serious infections especially in immunocompromised and/or hospitalized patients. Several A. baumannii strains are multidrug resistant and infect wounds, bones, and the respiratory tract. Current studies are focused on finding new effective agents against A. baumannii. Phage therapy is a promising means to fight this bacterium and many studies on procuring and applying new phages against A. baumannii are currently being conducted. As shown in animal models, phages against multidrug-resistant A. baumannii may control bacterial infections caused by this pathogen and may be a real hope to solve this dangerous health problem.

Keywords: Acinetobacter baumannii – Bacteriophages – Phage therapy – Multidrug resistance (MDR)
Notes

Acknowledgements

This work was supported by the statutory funds from the Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences. The authors also thank to Norbert Łodej for making figure to this paper.

 

Compliance with Ethics Standards

Conflict of interest

Andrzej Górski, is co-inventor of patents owned by the Institute and covering phage preparations. Other authors declare that they have no conflict of interest.

Animal and Human Rights Statement

This article does not contain any studies with human or animal subjects performed by any of the authors.

Keywords: Antibiotics; Drugs Resistance; Acinetobacter baumannii; Bacteriophages.

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Filamentous #bacteriophages are associated with chronic #Pseudomonas #lung #infections and #antibiotic resistance in #cysticfibrosis (Sci Transl Med., abstract)

[Source: Science Translational Medicine, full page: (LINK). Abstract, edited.]

Filamentous bacteriophages are associated with chronic Pseudomonas lung infections and antibiotic resistance in cystic fibrosis

Elizabeth B. Burgener1,*, Johanna M. Sweere2,3, Michelle S. Bach2, Patrick R. Secor4, Naomi Haddock3, Laura K. Jennings4, Rasmus L. Marvig5, Helle Krogh Johansen6,7, Elio Rossi6, Xiou Cao2, Lu Tian8, Laurence Nedelec9, Søren Molin10, Paul L. Bollyky2,3,† and Carlos E. Milla1,†

1 Center for Excellence in Pulmonary Biology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA. 2 Division of Infectious Diseases and Geographic Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA. 3 Stanford Immunology, Stanford University, Stanford, CA 94305, USA. 4 Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA. 5 Center for Genomic Medicine, Rigshospitalet–Copenhagen University Hospital, Copenhagen, Denmark. 6 Department of Clinical Microbiology, Rigshospitalet, Copenhagen Ø, Denmark. 7 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark. 8 Biomedical Data Science Administration and Statistics, Stanford University, Stanford, CA 94305, USA. 9 Primary Care and Population Health, Stanford University, Stanford, CA 94305, USA. 10 The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Lyngby, Denmark.

*Corresponding author. Email: eburgener@stanford.edu

† Co-senior authors.

Science Translational Medicine  17 Apr 2019: Vol. 11, Issue 488, eaau9748 / DOI: 10.1126/scitranslmed.aau9748

 

Infection-boosting phage

Chronic Pseudomonas aeruginosa infection is common in patients with cystic fibrosis (CF). Filamentous bacteriophage (Pf phage) can infect P. aeruginosa and has been shown to contribute to the virulence of infection in animal models. However, whether Pf phage plays a role in the pathogenicity of P. aeruginosa in CF is unknown. Now, Burgener et al. showed that Pf phage was abundantly expressed in sputum samples from two large cohorts of patients with CF. The presence of Pf phage was associated with increased antibiotic resistance and reduced lung function. The results suggest that Pf phage might play a role in the pathogenicity of P. aeruginosa infection in CF.

 

Abstract

Filamentous bacteriophage (Pf phage) contribute to the virulence of Pseudomonas aeruginosa infections in animal models, but their relevance to human disease is unclear. We sought to interrogate the prevalence and clinical relevance of Pf phage in patients with cystic fibrosis (CF) using sputum samples from two well-characterized patient cohorts. Bacterial genomic analysis in a Danish longitudinal cohort of 34 patients with CF revealed that 26.5% (n = 9) were consistently Pf phage positive. In the second cohort, a prospective cross-sectional cohort of 58 patients with CF at Stanford, sputum qPCR analysis showed that 36.2% (n = 21) of patients were Pf phage positive. In both cohorts, patients positive for Pf phage were older, and in the Stanford CF cohort, patients positive for Pf phage were more likely to have chronic P. aeruginosa infection and had greater declines in pulmonary function during exacerbations than patients negative for Pf phage presence in the sputum. Last, P. aeruginosa strains carrying Pf phage exhibited increased resistance to antipseudomonal antibiotics. Mechanistically, in vitro analysis showed that Pf phage sequesters these same antibiotics, suggesting that this mechanism may thereby contribute to the selection of antibiotic resistance over time. These data provide evidence that Pf phage may contribute to clinical outcomes in P. aeruginosa infection in CF.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
http://www.sciencemag.org/about/science-licenses-journal-article-reuse

This is an article distributed under the terms of the Science Journals Default License.

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Cystic fibrosis; Bacteriophages.

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#Lysocins: Bioengineered #Antimicrobials that Deliver #Lysins Across the Outer Membrane of Gram-Negative #Bacteria (Antimicrob Agents Chemother., abstract)

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

Lysocins: Bioengineered Antimicrobials that Deliver Lysins Across the Outer Membrane of Gram-Negative Bacteria

Ryan D. Heselpoth, Chad W. Euler, Raymond Schuch, Vincent A. Fischetti

DOI: 10.1128/AAC.00342-19

 

ABSTRACT

The prevalence of multidrug-resistant Pseudomonas aeruginosa has stimulated development of alternative therapeutics. Bacteriophage peptidoglycan hydrolases, termed lysins, represent an emerging antimicrobial option for targeting Gram-positive bacteria. However, lysins against Gram-negatives are generally deterred by the outer membrane and their inability to work in serum. One solution involves exploiting evolved delivery systems used by colicin-like bacteriocins (e.g., S-type pyocins of P. aeruginosa) to translocate through the outer membrane. Following surface receptor binding, colicin-like bacteriocins form Tol- or TonB-dependent translocons to actively import cytotoxic domains through outer membrane protein channels. With this understanding, we developed lysocins, which are bioengineered lysin-bacteriocinfusion molecules capable of periplasmic import. In our proof of concept studies, components from the P. aeruginosa bacteriocin pyocin S2 responsible for surface receptor binding and outer membrane translocation were fused to the GN4 lysin to generate the PyS2-GN4 lysocin. PyS2-GN4 delivered the GN4 lysin to the periplasm to induce peptidoglycan cleavage and log-fold P. aeruginosa death with minimal endotoxin release. While displaying narrow-spectrum antipseudomonal activity in human serum, PyS2-GN4 also efficiently disrupted biofilms, outperformed standard of care antibiotics, exhibited no cytotoxicity towards eukaryotic cells, and protected mice from P. aeruginosa challenge in a bacteremia model. In addition to P. aeruginosa, lysocins can be constructed to target other prominent Gram-negative bacterial pathogens.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Pseudomonas aeruginosa; Bacteriophages; Lysins; Bacteriocins; Lysocins.

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