MicrobiologyBytes

A recent paper in Trends in Microbiology examined the possibilities for using bacteriophages in controlling biofilms which might result in healthcare-associated infections (Preventing biofilms of clinically relevant organisms using bacteriophage. 2009 Trends in Microbiology 17: 66-72). Biofilms are firmly attached microbial communities in which the organisms produce an extracellular polymeric matrix. Biofilm organisms might cause disease by detachment of individual cells or clumps of cells, by production of endotoxin, or by providing a niche for the development of antibiotic-resistant organisms. Biofilm organisms are usually tolerant to antimicrobial agents and the treatment of indwelling medical device-associated infections with systemic antimicrobial agents is usually ineffective.

Bacteriophages have been used for the treatment of infectious diseases in plants and animals, although few clinical trials with stringent negative controls have been carried out. There is a renewed interest in phage therapy in light of growing concerns with antimicrobial resistance in healthcare institutions worldwide. The use of phages for the treatment of device-associated infections could reduce the use of antibiotics and might limit the spread of resistant organisms.

There is some evidence for the potential of phages in biofilm control. Bacteriophage T4 phage was effective against E. coli biofilms in a glucose-limited chemostat, although the rate of phage synthesis and assembly were directly proportional to the amount of protein synthesis in the host cell. Some phages produce polysaccharide depolymerases that have the potential to degrade the biofilm matrix.

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However, there are several important characteristics of phage that should be considered when evaluating the potential of phages to control clinically relevant biofilms. The specificity of receptors for a single phage strain will determine its host range; some phage have specificity at the strain level, such as strain typing phages, whereas some are more broad-spectrum and can infect multiple strains or related species. This high degree of specificity could be a drawback, especially in the case of polymicrobial biofilms.

Few studies have explored the role of biofilms in the development of phage-resistance. Phage cocktails developed via the isolation of host range mutants and broad spectrum phage could be advantageous. Another important question is how a patient’s immune system will respond to the therapeutic introduction of phage. Phages are antigenic and elicit a response by serum antibodies and the cellular immune system. Repeated exposure to the phage results in increasing antibody titers and studies in animal models have shown that phage is cleared from the bloodstream by the cellular immune system. In a short-lived treatment, the antibody response to phage is weak except in cases were serum antibody titers are present before phage treatment. It is possible, although unproven, that phage might associate with biofilms and thereby be protected from inactivation. It might also be possible to design mutant phages with enhanced ability to resist clearance by the cellular immune system.

Related:

• Biofilms
• Saturday Cimema: Bacteriophage Therapy
• Bacteriophages for plant disease control
• Coevolution with viruses drives bacterial mutations

A surprising example of interspecies competition is the production by certain bacteria of hydrogen peroxide at concentrations that are lethal for others. A case in point is the displacement of Staphylococcus aureus by Streptococcus pneumoniae in the nasopharynx, which is of considerable clinical significance. How it is accomplished, however, has been a great mystery, because H₂O₂ is a very well known disinfectant whose lethality is largely due to the production of hyperoxides through the abiological Fenton reaction. In this report, we have solved the mystery by showing that H₂O₂ at the concentrations typically produced by pneumococci kills lysogenic but not nonlysogenic staphylococci by inducing the SOS response. The SOS response, a stress response to DNA damage, not only invokes DNA repair mechanisms but also induces resident prophages, and the resulting lysis is responsible for H₂O₂ lethality. Because the vast majority of S. aureus strains are lysogenic, the production of H₂O₂ is a very widely effective antistaphylococcal strategy. Pneumococci, however, which are also commonly lysogenic and undergo SOS induction in response to DNA-damaging agents such as mitomycin C, are not SOS-induced on exposure to H₂O₂. This is apparently because they are resistant to the DNA-damaging effects of the Fenton reaction. The production of an SOS-inducing signal to activate prophages in neighboring organisms is thus a rather unique competitive strategy, which we suggest may be in widespread use for bacterial interference. However, this strategy has as a by-product the release of active phage, which can potentially spread mobile genetic elements carrying virulence genes.

Killing niche competitors by remote-control bacteriophage induction. PNAS USA January 13, 2009

Related:

• Pneumococcus: the quorum-sensing killer
• New Insights Could Lead to a Better Pneumococcal Vaccine
• Bacteriophage lysogeny
• Incidence of bacteriophage lysogeny in temperate and extreme soil environments

Huge numbers and variety of bacteriophages exist on our planet. In this article in Microbiology Today, Graham Hatfull describes this massive reservoir of unidentified genetic information:

You may well be under the impression that the largest number of undiscovered species – and the greatest pool of unknown genes – lie within the considerable biodiversity of the tropical rain forests. Not so. A compelling argument can be made that the biggest reservoir of unidentified genetic information is all around us, in the global population of bacteriophages.

Read more

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• MicrobiologyBytes: Bacteriophages
• Bacteriophages for plant disease control
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My colleague at the University of Leicester, Dr Martha Clokie, has recently co-edited a two-volume book on how to work with bacteriophages. Ranging from the evolution of pathogenicity to oceanic carbon cycling, the many and varied roles that bacteriophages play in microbial ecology and evolution have inspired increased interest within the scientific community. The book pulls together the vast body of knowledge and expertise from top international bacteriophage researchers to provide both classical and state-of-the-art molecular techniques, including laboratory protocols and a notes section which details tips on troubleshooting and avoiding known pitfalls. Volume 1 “Isolation, Characterization, and Interactions” examines a number of topics, including the isolation of phages, morphological and molecular characterization, and interaction with bacteria. Volume 2 “Molecular and Applied Aspects” examines bacteriophage genomics, metagenomics, transcriptomics, and proteomics, along with applied bacteriophage biology.

Bacteriophages: Methods and Protocols, Volume 1: Isolation, Characterization, and Interactions
Editors: Martha R.J Clokie, Andrew M. Kropinski
Methods in Molecular Biology , Vol. 501
ISBN: 978-1-58829-682-5 (Hardcover)

Bacteriophages: Methods and Protocols, Volume 2: Molecular and Applied Aspects
ISBN: 978-1-60327-564-4 (Hardcover)