Profile: Bacteria’s natural born killers

Just before Christmas last year, a 60-year-old patient at Westmead Hospital got some good news. The woman was suffering from a chronic infection that nothing could shift.

Pseudomonas aeruginosa had taken up residence in her bladder and all of the available antibiotics proved useless. She was facing a decision: radical surgery or a new therapy that has been rarely tested in a western hospital.

She opted for the latter. Over five days just before Christmas 2007, she was infused with a cocktail of bacteriophages through a catheter. Bacteriophages are viruses that infect bacteria and represent the most prolific organism on the planet.

Phages are natural born bacteria killers and are nature’s solution to keeping bacteria in check. They are ancient, they are everywhere and there are an estimated 1031 of them in existence.

The patient began to feel better within a couple of days and was home for Christmas. Six months after her treatment, she remains infection-free.

Not only was this good news for the patient, but good news for the private Sydney company that is developing bacteriophage therapy, Special Phage Holdings(SPH), run by Dr Tony Smithyman.

Phage therapy is nothing new of course, having been used extensively in the countries of the former Soviet Union for close to a century. It is most definitely coming back into fashion in the west, however, as it represents a radically different – and safe - alternative to antibiotics.

Smithyman and his team at SPH have been investigating phage therapy for the last five years. They have managed to refine their technology for collecting, screening and growing phages, and now have a library of several hundred, all specific to particular bacteria and even specific to strains of bacteria.

“They are commonly found in soil, water, plants, sewage, mud – anywhere there is bacteria that they can go and eat,” Smithyman says.

“The question is, how do you get them? You’ve got to go looking for them in the most appropriate places, which means a lot of interesting times. For instance, we go looking in Manly lagoon and Hubert (SPH’s marketing manager, Hubert Mazure) has been on a sewage mission.

“However, you have to have the right systems to extract the phages. There is quite a lot of skill involved. It’s a bit like looking for monoclonal antibodies – you have a target and then you screen. And the longer you go the better you get.”

Bacteriophages come in two forms: lytic and lysogenic. Lytic phages have evolved purely to destroy bacteria, Smithyman says. “There is no messing around with them. They go straight in and destroy the bacteria, and because of that they have fairly small genomes.

“The lysogenic phages have evolved to live with the bacteria, so they have larger genomes and have a different lifecycle. They can transfer toxin genes to the bacteria, so one of the things we have to do in phage therapy is have a system for screening to make sure you don’t have the lysogenic ones.”

Smithyman recently returned from a phage conference in Edinburgh with tales of some of the fascinating research being done with phages throughout the world. Surprisingly, it was the business sector rather than academics that first took the idea of phage therapy and decided to run with it, but Smithyman says the universities are quickly catching up.

“They are looking at using phages for delivering vaccines, a lot of work on using phages for purification and more genetic work coming through to help understand the molecular biology. And then there is the clinical work. A lot of that is very interesting. It is an intrinsically fascinating topic.”

---PB--- Classification and commercialisation

One of the issues phage therapy will face in the future is its categorisation for human health purposes. There are already phage therapy products on the market, but they are for plant health and to treat foodstuffs such as meat and cheese.

Those products were approved by the US FDA as Generally Regarded as Safe (GRAS), and this designation is expected for any future phage therapy product for humans.

“When it comes to treating patients, they aren’t a pharmaceutical so there is a lot of discussion around the world as to where they actually sit,” Smithyman says. “It may be that they will end up in their own category.

“They are extremely safe with no side-effects and no toxins, so there is no real need to go through animal studies, but the jury is still out on how they will be classified. It will probably be as a biological, not a chemical, but they might have to have their own category.”

Special Phage Holdings is one of a number of companies planning clinical trials for phages. The therapy has been used in parts of Europe, particularly in the world’s centre of excellence for phage therapy, Georgia, for most of the 20th century.

Smithyman says there are several American and UK companies in the Phase II trial stage, and there are university and clinical groups in France, Germany, the UK and Poland who are treating patients.

This is why both the successfully treated patient and the BioFirst Commercialisation award have come at exactly the right time for SPH. Smithyman says his company is at the stage of developing cocktails of phages for prototype products and was planning for the trial stage when the patient at Westmead came up.

SPH has strong research links with both Westmead and Royal North Shore Hospital, and has many international collaborators, and is planning a number of trials.

“We are planning trials now and working on the protocols,” he says. “We have three trials planned – one in Australia, again through Westmead and Royal North Shore; one overseas; and one a veterinary trial, also here in Australia.”

The company is also undertaking a second round of fundraising, approaching the group of original shareholders who provided the initial seed money, as well as sophisticated private investors and select corporate investors. The NSW Government award has come as a nice bit of publicity at exactly the right time, Smithyman says.

“We are going to be able to use the award to travel, there is some legal and patent advice and some accounting advice, as well as PR, so we’ll use them all very judiciously. It has come at exactly the right time.”

---PB--- Broad spectrum delivery

Smithyman foresees a time when broad spectrum phages will be developed for immediate use once a patient presents with an infection. He also sees a time when patient-specific phages are produced for particular infections.

“If it is extremely urgent they will be hit with a broad spectrum, but before that you take a swab and isolate the type of infection, take that isolate and run it past a vast collection of phages, choose the right one and then grow it up quickly. In a couple of days the patient can be treated with their own specific phages.”

Delivery options are as versatile as the phages, he says. “The patient at Westmead was infused because we had to decide how to get the phages into the bladder, so a catheter was chosen. But normally they would be used in liquid form embedded in bandages, or as a tablet for straightforward oral delivery. We have also formulated a cream, and another way they will be used is through a nebulliser.”

Phages are extraordinarily powerful but obviously they won’t cure everything, particularly if there are co-morbidities. And they probably will meet the brick wall of bacterial resistance, just as antibiotics have done.

“That’s why we are developing cocktails – bacteria might become resistant to one type of phage, but not to many.”

And the market is potentially huge. As Smithyman points out, the large pharmaceuticals have been walking away from trying to develop new antibiotics over the last couple of years because there isn’t much profit in it, leaving it up to the smaller and generic pharma companies to look for biotechs to come up with novel ideas for antibiotics.

It is a $24 billion a year sector that is becoming a vacuum, he says, and perhaps phages are the right organism to fill it.