Review Article Phage Therapy: Eco-Physiological Pharmacology
Phage therapy - pdfs.semanticscholar.org · •Phage therapy trials without serious side effects or...
Transcript of Phage therapy - pdfs.semanticscholar.org · •Phage therapy trials without serious side effects or...
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Phage therapy
Institute of Molecular Biomedicine
Comenius University, Faculty of Medicine
www.imbm.sk
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Outline
• Introduction
• Taxonomy
• Cycles of phages
• Bacterial resistance
• Phage therapy
• Conditions for phage therapy
• Enzybiotics
• Phages in other industries
• Phage typing
• Phage display
• Bacterial sensing
• Future outlook
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Microbiome
• Total microorganisms, their genomesand ecosystem in/on the human body
• Together „supraorganism“
• New genes with advantages
• Mouth, skin, gut...
• Unique ecosystems
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Human cellsBacterial
cells
We are bacteria
10 13 10 14
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• „core microbiome“
• „variable microbiome“
• Personalized medicine
• Host´s physiology
• Health status
HUMAN MICROBIOME
PROJECT 2007
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Mammalian virome
• Viruses of eukaryotic cells (e.virome)
• Bacteriophages infecting bacterial cells (b.virome)
• Viruses of archea (a.virome)
• Virus-derived genetic elements in host chromosomes
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1031 members of virome1% explored
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Bacteriophages
• Most abundant entities in biosphere
• Viruses specific for bacterial cells
• Distribution according to their hosts
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Where can we find phages ?
• Everyday life
• Soil
• Sewage
• Food
• Water
....
• Everywhere where bacteria are present
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Taxonomy• ICTV (not CVTI ) International Committee for Taxonomy of Viruses
• Up-to-date taxanomic guidelines
Tailed bacteriophages order CAUDOVIRALES
Three families Myoviridae
Siphoviridae
Podoviridae
Different genera
13 families and 31 genera
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• Diverse genome size
• ss DNA, ds DNA or ss RNA, ds RNA
• Phage particles (VIRIONS) lipoprotein
or protein coat
• Tails
• ~ 200 nm
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Life cycles of phages
• Lytic
• Lysogenic
• Pseudolysogenic
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Phage therapy• Therapeutical usage of bacteriophages for treating bacterial infections
• Long history (1915/1917)
• Some approvals
• Georgia, Russia and Poland
Frederick Twort Félix d´Herelle
• Medicine, dentistry, veterinary science and agriculture
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Mechanisms of antibiotics
• Cell wall synthesis
• Protein synthesis
• Nucleic acid synthesis
• Cell membrane functions
• Metabolism
• Others
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Resistance of bacteria
• Antibiotics vs. multidrug resistant bacterial strains
• Biofilm
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Resistance of bacteria
• Absence of a susceptible target
• Multidrug resistance effluxpumps
• Mutations
• Transformation
• Modification of target site
• Direct antibiotic inactivation
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Lack of new antibiotics or effective treatment !!!
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Phage therapy renaissance
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Pros and cons of bacteriophage therapy
• Bacteriophages infect only bacterial cells
• Bacteriophages are capable
of self-replication and self-elimination
• Bacteriophages with narrow host range
• Phage therapy trials without serious side effects or allergic reactions
• Single dose would be sufficient to cure the patient
• Bacteriophages in combination with antibiotic therapy may lower the occurrence of bacterial resistance
• Bacteriophages are highly species-specific, it is necessary to precisely characterize the infectious bacterial agent prior to their application
• Phage defined in vitro environment asstrictly lytic, could change this cycleunder the physiological conditions of the human body
• Possibility of toxic shock after the bacterial lysis and subsequent amplification of neutralizing antibodies during the re-treatment of the patient
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Prerequisites for phage therapy
• Host range
• Purity of phage preparations
• Clearance of phage therapeuthics
• Lysogeny in vivo
• Complete phage characterization (genes, receptors ... host-phageinteractions ..., )
• Safety testing !!!
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Commercial products
PhagobiodermBiophage-PA
Routes of administration
OralTopicalIntravenous
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Phages in agriculture
• Intralytix, Inc. (http://www.intralytix.com)
• EBI Food Safety (http://www.ebifoodsafety.com)
• Omnilytics, Inc. (http://www.omnilytics.com)
• Sevapharma, a.s.(http://www.sevapharma.cz)
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Enzybiotics
• Hybrid name lytic enzymes + antimicrobial potential
• Enzymes able to cause microbial cell death
Endolysins (from phages)
Bacteriocins (from bacteria)
Autolysins (from bacteria)
Lysozymes (various organisms)
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How endolysins work?
• Enzymatic cleavage of bacterial cell wall peptidoglycans (cell lysis)
• ds DNA phages
• end of the lytic cycle
(1) N-acetylmuramoyl-L-alanine amidases;
(2) endopeptidases;
(3) N-acetyl-β-D-glucosaminidase;
(4) N-acetyl-β-D-muramidases (lysozymes)
(5) lytic transglycosylases
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Methods: Vectors in MB
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Methods: Phage typing
• Used for identification and differentiating of bacterial pathogens
• Lysis due to viral infection is specific
• Bacteriopage-based diagnostics
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Methods : Bacteria sensing
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Biosensors advantages
• Sensitive, rapid and selective detection
• Cost-effective and portable
• Lower limit of detection
• Minimum sample preparation
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Methods : Phage display
More information by J.B.
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Future outlook
• Large range appplication of phages in molecular biology,
biotechnology and medicine ! ! ! ! !
• Safety and efficacy issues
• Unexplored entities
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Thanks for Your attention !