Bacteriophages - a replacement for antibiotics

11 February 2003

Published in The Age

For half a century, antibiotics have been the “nuke” in medicine’s infection-fighting armory. But, unhappily, doctors have recklessly over-prescribed them, and the bugs they combat can evolve rather quickly. So now many bacteria - the so-called “superbugs” - have developed a resistance to antibiotics.

Superbugs contribute to the deaths of 7,000 Australians annually. The trend is expected to accelerate sharply: indeed the American Society of Microbiology recently testified to Congress of “the end of the antibiotic era”.

In response, several alternative approaches to infection-fighting have appeared - including strengthening natural immunity (the holistic approach), and an exciting new antimicrobial from the Australian company Chemeq.

But in Tbilisi, Georgia (former USSR), the Eliava Institute has been attacking the problem for 80 years. Their agent is the humble bacteriophage - a bacteria-killing virus which may be the most prevalent life-form on Earth. Phages (as they’re known) attach to a bacterial cell, penetrate it with their tail, and inject it with their DNA. Inside the cell, they multiply so prolifically that the cell soon bursts and dies - spreading more phages to kill more bacteria.

Phages were discovered in 1915 by British bacteriologist Frederick Twort, and independently in 1917 by Canadian microbiologist Dr Félix d’Hérelle. In 1919, d’Hérelle treated several children with severe dysentery, curing them literally overnight. Phages went on to defeat staphylococcal skin infections, typhoid, cholera and urinary tract infections.

In 1923 the Eliava Institute was founded by D’Herelle and Georgian microbiologist George Eliava. The Institute’s work was often done in appalling conditions, and there was a multitude of technical problems. Eliava was murdered by Stalin in 1937.

Phages did not make the progress they could have. Then, in the early 1940s, penicillin arrived - and they were largely forgotten.

The Eliava Institute plugged on - even after most of its funding disappeared with the USSR. Soon, predatory foreign companies made approaches.

“Our contacts with companies have been extremely disappointing”, says Nina Chanishvili of Eliava. “Therefore we prefer the public foundations, which pay good money and put much less pressure on us.”

The best-known of these is the PhageBiotics Foundation, in Washington State, which is raising money to help put the Eliava Institute back on its feet. Its head, Dr Elizabeth Kutter, has been working on the molecular biology of phages since 1963:

“Phages are extremely promising,” Kutter enthuses, “particularly for such things as diabetic ulcers and osteomyelitis. Also deep wound infections, where tissue damage means that antibiotics can’t get into the infected area: phages, which multiply in the first susceptible bacteria they find, keep multiplying and working their way deeper into the problem area with each new burst that is released. For example, people virtually never have to undergo amputations due to diabetic foot problems where surgeons who use phages are available.”

A scientist who has done “ground floor” research on phages is Dr Carl Merril, chief of Biochemical Genetics at the US National Institutes of Health. In 1994 Merril experimented with specially designed “long-circulating phage variants”, which reduced symptoms and sped recovery time compared to “wild” phage strains.

Merril says experiments suggest that germ-resistance is less of a problem with phages than it is with antibiotics: “Furthermore, the phage-resistant bacteria mutants that were found in these experiments were less pathogenic.”

For some years Elizabeth Kutter has organised biennial international phage meetings - “the fifteenth of which will be held this July here at Evergreen State College” (Washington State).

“Now my major interest is to help phages move forward in the rest of the world. We are involved in collaborations with several groups in Tbilisi, to support them for grants from the International Science and Technology Centres, funded by the European Union, Japan and our State Department. We have also got drawn into some work related to diarrhoeal diseases in Bangladesh, and in trying to clean E. coli 0157 out of livestock. This highly pathogenic E. coli variant is in a quarter of the cattle in the US and Europe, and has caused various problems including massive beef recalls, contaminated unpasteurised apple juice, water contamination and deaths.”

Dr Kutter foresees “wonderful” possibilities for phages, especially “for lung, gut, diabetic ulcers, burns and wounds”.

Dr Richard Carlton, another leading US phage researcher, has formed a New York-based company - Exponential Biotherapies - to develop phage products for a market he believes is materialising from the decline of antibiotics:

“The emergence of multi-drug-resistant bacteria,” Carlton says, “means that nowadays people are dying from infections that, just five or ten years ago, any medical student could have cured.”

And phages may be a better product anyway: “Phages multiply exponentially as they kill the bacteria. In contrast, antibiotics are metabolized as they work.”

Dr Carlton foresees “a very large market” for phages - “in the human health sector, companion and farm animals, and also decontaminating food processing facilities”.

Someone else who is working to turn this promise into commercial reality is Dr Glenn Morris of Intralytix in Maryland, USA - a small biotech firm which has a number of phage-related patents pending.

In addition to providing an alternative in an age when antibiotics are increasingly failing us, Morris agrees that phages may also be vital to the “disinfection of environmental surfaces and food, with the increasing concerns about widespread use of chemical disinfectants”.

Morris believes that phages’ specificity to individual bacteria is a key strength: “Basically, they are ‘programmed’ to attack only a single strain of bacteria - not even all strains within a single species. Antibiotics, in contrast, will generally kill entire classes of bacteria.” This leaves us depleted of many “good” bacteria.

Phages have few side-efects, and they’re relatively cheap to produce - making them especially useful in the developing world. So, is there anything wrong with them?

Dr Morris joins other scientists in cautioning that, because of their specificity, phages “are not that useful for ‘empiric’ therapy - that is, therapy that is initiated before one knows which bacteria are responsible for an infection”.

He also believes that germ-resistance is a reality, even for phages. But it can be minimised, he believes, “by simultaneously using multiple different phages against any one bacteria - ‘phage cocktails’ - and by withdrawing phages from use when resistance begins to appear.”

For Dr Elizabeth Kutter the sky’s the limit: “There are a few bacteria for which no phages have yet been found,” she says. “But few doubt that phages exist there, and some will eventually be found.”

Meanwhile at Eliava, where it all began, times are still tough, despite some Western support. “There are about 100 persons on the staff,” says Nina Chanishvili, “the majority of whom are not supported by the foreign grants. Their salaries often do not even attain the level of ‘sustainable’, as estimated by the special office of the United Nations, which is $US50-60 per month.”

As well as applying for further foreign grants, Eliava is trying to attract overseas partners for shared projects at diverse locations. It’s also struggling to free itself of the impact of a government which for 70 years was venal and incompetent - and which is now bankrupt. Renovating its labs and modernising its equipment is high on its list of priorities.