Not all viruses: Bacterial viruses against canine pyoderma

Issue 72 | April 24, 2020
9 min read
Capsid and Tail

Dogs will be happy to hear that phages may one day be available for them, too. Photo credit: John Price, Unsplash.

Phages for dogs too? This week, Stephanie Lynch, a PhD candidate at La Trobe University in Melbourne, Australia, tells us about her research into phages and endolysins to treat multidrug-resistant Staphylococcus pseudintermedius infections in dogs.

Also in this issue: a request for therapeutic E. coli phages, new ways prophages are running the show, why Klebsiella phage therapy may need extra caution, more info about how COVID-19 is likely impacting AMR, and more!

Urgent April 23, 2020

Urgent need for Escherichia coli phages for a patient

Phage Therapy Sepsis ESBL E. coli

We are urgently seeking Escherichia coli phages for a patient suffering from recurrent ESBL E. coli sepsis in Finland.​

Ways to help at this stage:

  • By receiving the strain and testing your phages
  • By receiving the strain and using it to search for new phages against the organism
  • By sending your phages for testing on the patient’s strain
  • By helping spread the word about this request
  • By connecting us with labs or companies you think we should contact

Please email [email protected] if you can help in any way, or if you would like further details/clarification.

Let’s make a difference,
Phage Directory

What’s New

Xiaolin Xiong (Wuhan University, China) and colleagues published their work on an unusual phosphorothioation-sensing bacterial defense system with broad anti-phage activities in Nature Microbiology.

Research paperPhage defense

A new study by Demeng Tan (Fudan University, China), Mads Frederik Hansen (Max Planck Institute for Terrestrial Microbiology, Germany) and colleagues have shown that a Vibrio anguillarum prophage is controlled by quorum sensing and stimulates its host to make biofilms at low cell densities. Behind-the-paper article | ISME Paper.

Research paperPhage-host interactionsProphage biology

Beatriz Osuna (UCSF) and colleagues published two new papers this week in Cell Host & Microbe: one on how Listeria phages protect their lysogenic genomes by inducing Cas9 degradation and the other detailing how a bifunctional Listeria phage anti-CRISPR tunes its expression in response to Cas9 levels.

Research paperCRISPRPhage-host interactionsPhage defense

Derek Cerchione and colleagues at Editas Medicine in Cambridge have developed a new M13 phage-based directed-evolution strategy and a mutagenesis method called SMOOT to engineer Cas9 nuclease activity. They report the isolation of a Cas9 mutant that reduces off-target cleavage while preserving efficient editing at multiple on-target sites.

Research paperCRISPRBiotech

Soumyananda Chakraborti (Jagiellonian University, Poland) and collaborators from Poland, UK and Canada report the characterization of NinH, encoded by bacteriophage lambda. NinH is the first example of a phage mimic of the bacterial Nucleoid-Associated Protein Fis, and potentially influences phage excision-integration events.

Research paperMolecular Biology

Andrea Rocker (Monash University, Australia) and colleagues published a study on how Klebsiella pneumoniae outer membrane porins affect its permeability to antibiotics. They suggest caution be taken when targeting this species and other carbapenem-resistant Enterobacteriaceae with phage therapy, since exposure to phages that select for altered porin expression may increase resistance to antibiotics.

Research paperMolecular BiologyAMR

Maryn McKenna wrote a new Wired piece on how the COVID crisis may worsen the AMR crisis. Within it, she links to a useful compendium of literature on secondary infections and AMR in the context of COVID-19, which was compiled by two researchers, Issra Bulgasim and Adam Roberts, at the Liverpool School for Tropical Medicine.

NewsPerspectiveAMRCOVID

Here’s a nice article on the ‘age of bacteriophage’ written by undergraduate students Muskan Gupta and Rohit Gokhale at Acharya Narendra Dev College in New Delhi. Included is some excellent phage art! This was written as part of an online training course in science writing provided by IndSciComm.

Science CommunicationUndergraduate Research

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Not all viruses: Bacterial viruses against canine pyoderma

Profile Image
PhD Candidate
La Trobe University

I am a third year PhD student from La Trobe University, Melbourne, currently isolating and researching the use of bacteriophages for skin infections in animals. I have a background in Animal & Veterinary Bioscience and hope to continue research of bacteriophages as therapeutics within the veterinary or livestock sector. I am also currently developing and optimising the use of animal-alternative models for safety and efficacy trials of phage therapy. I am always willing to chat about phage research and would like to connect with phage biotech companies as I am interested in jobs within the industry sector.

With COVID-19 giving viruses a bad rep, phage researchers have taken to twitter with the hashtag #NotAllViruses, and rightfully so! Bacteriophages (phages) are good viruses and are a promising alternative therapeutic against antibiotic-resistant bacterial infections. Their future use within the veterinary sector is promising, especially against infections such as canine pyoderma.

Antibiotic resistance within the veterinary sector is an important issue

Recent reports state 45% of bacterial isolates from companion animals are multidrug-resistant (MDR), able to survive administration of three or more different antibiotic classes!

One bacterium highlighted throughout this report, and the focus of our research, is Staphylococcus pseudintermedius, which causes a range of moderate to severe infections infection in dogs, where 78% of isolates are MDR. Of these infections, canine pyoderma is a significant concern, as it is the most commonly diagnosed skin infection within small veterinary practices.

With an increase in antibiotic resistance and a parallel decline in effective antibiotics, there is an urgent requirement for alternative therapeutics, with phage therapy explored as a novel treatment option in dogs.

Phages: a promising alternative in veterinary medicine

Did you know, the first successful trial of phage therapy in animals was conducted in 1919?

Fast forward 100 years and interest in phages has resurfaced due to the current antibiotic-resistance crisis. In 2010, Hawkins and colleagues conducted a successful phage therapy trial against Pseudomonas aeruginosa, an MDR bacterium that causes a chronic ear infection in dogs. Results showed the phage treatment reduced bacterial counts, which led to clinical improvement within 48 hours, and there we no signs of toxicity to the dogs.

With preliminary evidence of successful phage therapy in dogs, my research is focusing on phages and phage-derived products as a treatment for S. pseudintermedius infections in dogs.

The potential of phage therapy for Staphylococcus pseudintermedius

Phage therapy is an attractive option for the treatment of S. pseudintermedius infections in dogs, with a study by Moodley and colleagues already isolating four novel phages which preferentially lyse Methicillin-Resistant S. pseudintermedius (MRSP).

Additionally, as indicated by the TEM image below, we have isolated unique phages. They show narrow host ranges when tested individually, with an increase in lytic ability when combined in a phage cocktail, where they lyse 52% of S. pseudintermedius clinical isolates. Preliminary testing in vitro shows our phages significantly reduce bacterial counts within 20 minutes, with complete bacterial clearance by 2 hours.

Transmission electron micrographs (TEM) image of phage S. pseud_22s
Transmission electron micrographs (TEM) image of phage S. pseud_22s.

Despite this promising data, genome characterisation of ours, and of previously published phages, show genes associated with lysogeny, which is unfavourable for phage therapy. Therefore, our research now explores the potential of endolysins against S. pseudintermedius.

Endolysins

Endolysins are enzymes synthesised by phages at the end of their lytic lifecycle to degrade the bacterial peptidoglycan to release phage virions. Junjappa and colleagues have shown that purified endolysin treatment results in moderate clearance of Staphylococcal infections with no allergic reactions observed in dogs. Therefore, we are interested in the potential use of endolysins for S. pseudintermedius specific infections in dogs.

We have selected 6 endolysins from S. pseudintermedius phages which are currently being manufactured. Upon synthesis, we aim to test the lytic activity of the purified endolysins on our clinical strains of S. pseudintermedius.

However, for phages or endolysins to progress to clinical trials in dogs, extensive trials in animal models are required.

Silkworm (Bombyx mori) as an alternative animal model for phage therapy trials

Currently, mice models are used for the safety and efficacy of phage therapy trials, however, recently, there has been extensive research focused on the development of alternative animal models.

Interestingly, Takemura-Uchiyama and colleagues have shown the results generated using the silkworm (Bombyx mori) model reflect results generated in mice models.

Using silkworms at the 5th instar stage, as displayed in the image below, we have shown that S. pseudintermedius can survive and replicate within the silkworm and is able to kill the silkworm in a dose-dependent manner. We have also shown that injection of our phage preparations individually shows no adverse side effects to the silkworms and is, therefore, a safe treatment option moving forward and will progress to upcoming trials in dogs.

Silkworm at 5th instar stage, used for phage therapy trials.
Silkworm at 5th instar stage, used for phage therapy trials.

The future of phage therapy

Multi-drug resistant S. pseudintermedius is a significant threat within both veterinary and human health. The use of phages and endolysins, as well as the development of an alternative animal model, represents a significant step forward, and will set the groundwork for the progression of phage therapy into a clinical setting for the treatment of infections in dogs caused by S. pseudintermedius.


Rohit Kongari helped us produce this week’s article by helping us source and write the What’s New and Jobs sections. Thanks Rohit!!

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