Bacteriophage and biofilms
There is a requirement for science and technology to push towards advancement and offer medical solutions which, whilst addressing the difficult problems facing humanity in post Covid-19 era, are also safe. The use of Bacteriophage in medicine represents an old technology that has been forgotten a little. It has been used in eastern European countries to treat bacterial infection (Poland, Georgia) instead of antibiotics and now, when the world is challenged with Antimicrobial Resistance, bacteriophage has had a comeback with a promise to benefit many industries. A recent review summarises the state of play in medicine and other fields, e.g. the use of phage technology to treat catheter-associated urinary tract infections; in patients with osteomyelitis (infection of the bone) and in foot ulcers and other wound treatment; or the promise of new oral health products based on phages. [i]
As a consortium, NBIC’s academic partners bring together the latest research and long-standing expertise in this field; working in different areas of application of the phage technology across the industries e.g. biotechnology, agriculture, food manufacturing, personal care and veterinary or human clinical medicine.
Historical perspective on phage technology
“Bacteriophages, or phages for short, are viruses that infect and kill bacteria. Their potential as antibacterial agents was realised shortly after their discovery more than 100 years ago and for about 20 years phage preparations had been produced on large scale by pharmaceutical companies in Europe and elsewhere. Due to a number of factors, the efficacy of these early phage preparations (phage cocktails) was controversial, and with the introduction of antibiotics into clinical practice, the research into phage therapy was all but abandoned the West. The situation started to change in 2000’s, when the continuing emergence of multidrug-resistant bacteria necessitated the search for antibiotic alternatives, thus renewing the interest in bacteriophages”.
Approaching the health industry with phage technology
Phages can be effectively used in many applications as efficient, specific and environmentally safe bactericidal agents. Our partners have different capabilities in a range of biofilm research areas. The ongoing research at Queen’s University Belfast, is focused on investigation of bacteriophages and their enzymes as tools for microbiome manipulation and biofilm control and eradication. The research group are currently interested in the development of novel bacteriophage-based preparations for topical applications (mainly for treatment of skin and wound infections and infections of the genitourinary tract), they have expertise to isolate and propagate new bacteriophages, perform genome and transcriptome sequencing and bioinformatics analyses, conduct tests of antibacterial and anti-biofilm activity of phages, and are currently working towards establishing a platform for genetic engineering and synthetic biology of bacteriophages.
Medical application of this technology is noted in the research group of Professor Jeremy Webb from University of Southampton. His group has shown that phage plays an integral part of biofilm development and impact on bacterial virulence during infection. Bacteria predominantly live in high-density biofilm communities with significant interactions between phage and their bacterial host. Having characterised a new filamentous phage of Pseudomonas aeruginosa, named Pf4, the researchers studied its role in biofilm development[ii][iii] showing that it promotes survival in harsh environments, e.g. exposure to detergents, contributing to virulence in a mouse model of infection[iv]. Dr Franklin Nóbrega, who runs the Microbial Interactions Lab at the University of Southampton, focuses on the mechanisms phages use to redirect the bacterial metabolism for the production of more phages or bacterial replication, defence, biofilm formation and dispersal. In gut health, phages are major contributors to the success of faecal microbiota transplantation. Together with collaborators from the Amsterdam Medical Center, they investigate using virome (phage) transplantations. Further, creating a biobank of phages, bacterial strains, and genes to explore the mechanisms of phage resistance also support phage therapy in the UK for academics and interested health industries.
Antimicrobial resistance (AMR) presents a great challenge to the healthcare systems worldwide. In human health, the gut microbiome is a promising target area for phage therapy. At University of Warwick, Dr Eleanor Townsend works on projects studying both basic biology and clinical applications of phages in Klebsiella infections. She explains that,
“Klebsiella species are one of the pathogens highlighted by the WHO for their increasing antimicrobial resistance; they have ability to form robust biofilms. Phages have the potential to degrade these biofilms by breaking down the matrix that glues biofilms together. However, our research has shown that they are far better at preventing biofilms. We focus on two clinical areas, urinary catheter coatings to prevent biofilm formation leading to reduced need for antibiotic interventions and better outcomes for patients; and using phage to alter the gut microbiome. Klebsiella in the gut degrade meat and dairy foods into metabolites that damage cardiovascular health and by selectively removing or reducing Klebsiella, I aim to reduce the risk of cardiovascular disease”.
At Nottingham Trent University, Dr Samantha McLean’s research focuses on enteric bacteriophage as vectors for gene therapy against bacterial pathogens. The phage delivers anti-virulence genes to disable foodborne pathogens whilst leaving commensal gut flora intact; the phage or phage-derived products can remove bacterial capsules or break down biofilms in the gut.
In commercialisation of bacteriophage products, many challenges exist in terms of intellectual property (IP), regulatory requirements and an effective and reliable processes for bacteriophage production. The development of different bacteriophage products for the application as disinfectants in the food industry has probably been the most successful, and our theme for the next blog.
[ii] Webb JS, Lau M, Kjelleberg S. Bacteriophage and phenotypic variation in Pseudomonas aeruginosa biofilm development. J Bacteriol. 2004 Dec;186(23):8066-73. doi: 10.1128/JB.186.23.8066-8073.2004. PMID: 15547279;PMCID: PMC529096.
[iii] Rice SA, Tan CH, Mikkelsen PJ, Kung V, Woo J, Tay M, Hauser A, McDougald D, Webb JS, Kjelleberg S. The biofilm life cycle and virulence of Pseudomonas aeruginosa are dependent on a filamentous prophage. ISME J. 2009 Mar;3(3):271-82. doi: 10.1038/ismej.2008.109. Epub 2008 Nov 13. PMID: 19005496; PMCID: PMC2648530.
[iv] Whiteley M, Bangera MG, Bumgarner RE, Parsek MR, Teitzel GM, Lory S,Greenberg EP. Gene expression in Pseudomonas aeruginosa biofilms. Nature. 2001 Oct 25;413(6858):860-4. doi: 10.1038/35101627. PMID: 11677611.
Dr Katerina Steventon, NBIC Senior Innovation Consultant