Phage against the machine

Geoff Harper reports on the scientists fighting the war against antibiotic resistance

As featured in the media over the past couple of years or so, increasing antibiotic resistance could eventually mean that a hitherto simple effective treatment for infectious diseases will no longer be available. However, where there’s a will, there’s a way…

The current resistant bacterium on the radar is a strain of E. coli recently identified on farms in China as resistant to last-ditch antibiotic, colistin. It has already reached the UK and is now causing some alarm. Identifying an appropriate phage to kill the superbug is not considered a drawback by academics, but is unlikely to be used on patients anytime soon, which brings us to novel ways of delivering and using phages.

Martha Clokie, professor of Microbiology, the Department of Infection Immunity and Inflammation at the University of Leicester is confident that phages will exist for this strain: “E. coli is a good target for phage therapy, there is quite a lot of basic and applied science that needs to be done first though.”

Dr David Harper of Evolution Bacteriophages, reveals he is also pretty confident, given the ready availability of phage against E. coli, that such an approach would be viable. Paul Barrow, University of Nottingham whose team has been looking at E coli phages to counteract antibiotic resistance, says identifying a phage to address the new strain is not only possible but, ‘quite easy to do’.

But here’s the rub: pharmaceutical companies have been reluctant to invest in phage research, because without a patentable end product, development is not commercially viable. Furthermore, the manner by which phages attack their host, by breaking the walls of the bacteria and injecting them with their own DNA has complicated matters and although phages have been used safely in Georgia, Russia and Poland for years, Western medical authorities are less enthusiastic. Medical trials are ongoing, but it is a very slow process.

There may be hope in that if the bacteria could be destroyed at source, in the infected meat, there would not be a need to treat patients suffering from E. coli as a consequence of eating that product. Paul Barrow confirms the eradication of resistant bacteria in meat products is 'possible, certainly'.

Clokie explains there are many potential uses for both phages and phage products (products derived from phages that have the same effect): “The current regulatory framework is different for food products to anything medical, and thus this may dictate which products are developed first. There are some phage products for food and agriculture currently in use, and the medical regulatory authorities are being helpful in their capacity. I think there is a lot of scope for reducing contamination at source.  Also, different bacteria have different biologies and so there is likely to not be one universal answer.” Harper also confirms that both could be done using different phage sets: “The availability of multiple agents is one of the big strengths of phage.”

On 13 January 2016 the Wellcome Institute published a report in the Lancet on alternatives to antibiotics, which concludes that the alternatives will not be able to take over from conventional antibiotics and will probably be used alongside rather than replace them. The report also assumes the most promising alternatives, including probiotics and phages, will not be licensed for use and dispensed any time soon.

Rather than abandon such a promising treatment scientists have been devising imaginative ways to adapt and use phages or their derivatives in ways that are acceptable and within current regulations.

Spray away

One way would be to use a phage spray on various foods including livestock carcasses as an intervention, so deal with the problem at source. One such product designed specifically for the elimination of E. coli on meat is called Ecoshield from Intralytix. Dr Alexander Sulakvelidze, the company’s vice-president, R&D and chief scientist claims its products can be adapted to deal with mutant bacteria: “Phage preparations can be updated to adapt quickly to address new antibiotic-resistant strains,” he confirms. “The mode of action of phages differs from those of antibiotics, and the mechanisms of resistance against phages are different from those for resistance to antibiotics. Thus, phages can kill many bacterial strains that cannot be killed by antibiotics (ie, antibiotic-resistant strains). The same concept applies to E. coli. Whether or not the approach is successful in real life depends on many factors of course, but it certainly can be very effective for at least some infections when phage treatment regimen is well established and phages are properly administered.”

The revival

Another way is to revive redundant antibiotics to make them effective once more. Scientists at Nottingham and Cambridge Universities have devised a way of altering antibiotic-resistant bacteria to remove their protection against existing drugs. As a result the efficacy of our remaining antibiotics could be restored without the immediate necessity of developing new ones.

This highly creative strategy neatly sidesteps the problems associated with development of new antibiotics and alternatives. Bacteriophages (phages for short) have long been regarded as promising weapons against resistant bugs. First discovered 100 years ago, they are viruses that target and destroy specific bacteria highly effectively. Phages and derivative products have been put forward as a practical alternative to conventional antibiotics for some times, but researchers have now found they may enable existing drugs to kill otherwise resistant bacteria without having to destroy them themselves.

Professor Paul Barrow leads a team at the University of Nottingham exploring the use of phages against bacterial infections including those that are resistant to antibiotics. Barrow explains: “What we are proposing is that the genomes of bacteriophages may be altered to include a genetic system which is able to down regulate expression of antibiotic resistance genes or to inactivate these genes, such that when the phage attaches to the resistant bacterium and injects its DNA, rather than preparing to multiply into many copies of the phage genome resulting in bacterial death, it reduces the antibiotic resistance of the bacterium and makes it more susceptible to antibiotic use. This may lengthen the "shelf life" of existing antibiotics. There are some situations where this might be preferable to killing the bacterium.”

A report for the UK Government in December 2015 warned that drug-resistant bacteria could kill 10 million people a year by 2050 with an economic cost of trillions. It is, therefore, critical that the world’s armoury against superbugs is augmented as soon as possible. Time is running out.

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