24 February 2011

What is the next penicillin?

Cosmos Online
Antibiotics will only remain useful for so long and new approaches to infectious disease management need to be considered. Is there a way we can force the bacteria to get sick so they cant do the same to us?

Credit: iStockPhoto

Human viral diseases are a big deal. They cause millions of deaths every year, a huge amount of illness and the resulting social and economic implications are staggering.

But we are not alone in our suffering. Bacteria are afflicted with viruses too.

Bacterial viruses or bacteriophage (phage for short) do to bacteria exactly what viruses do to our cells – invade, usurp and destroy. This begs the question, ‘why are we not killing bacteria with phage all the time?’ and it’s a good question to ask.

Phage are largely ignored by the human immune system, cheap to produce in large numbers and target only the bacterial species that is causing the disease.

As a result these little viruses are poised to be the next penicillin, and rather than to simply replace it, they may bring all the benefits of penicillin without some of the major drawbacks.

Phage make up a huge amount of the biomass of the Earth. In one millilitre of seawater you can find 9 × 108 viruses and up to 90% can be bacteriophage. That means that the oceans alone may contain up to 1.02 × 1033 bacteriophage, even as a conservative estimate.

Viruses, like all organisms, exist to replicate but viruses cannot replicate autonomously. Viruses and bacteriophages require the machinery of a cell in order to copy and manufacture their body components. For phage the cell must be bacterial.

Two types of phage exist and each uses the cell differently to produce huge numbers of phage particles. Lysogenic phage push their DNA into the bacterial chromosome and can sit dormant or slowly produce phage over time.

They can also enter the lifecycle of the other type of phage – the lytic phage. Rather than hijack the bacteria and use it as a perpetual phage factory, lytic phage overwhelm the bacterium (similar to the way our cells are over run by viruses) and forces continual phage replication. The bacteria are filled up with phage until they explode.

It’s this process that makes them a powerful option for potential therapy development.

Phage were first detected way back in the very early 20th and early work moved swiftly. Although detected, phage remained invisible even through microscopes until the 1940’s, when we could actually visualise the bacteriophage.

Of particular importance was the work of the Frenchman Félix d’Herelle based at the Pasteur Institute in France who developed the field of phage biology throughout his life always continuing to push it forward.

D’Herelle was a self-taught microbiologist who discovered phage (or the ‘invisible microbe’ as he called them) in 1916 while examining the stools of French soldiers suffering from bacillary dysentery.

He found that phage started to appear as the dysentery started to clear up and he made a connection – could the phage be removing the bacteria?

D’Herelle collected a number of stools and made cultures from them to try collect the phage. He found that, sure enough, when he then mixed his phage culture with very dense cultures of Shigella (the bacterial species causing the dysentery), that the bacterial culture would dissolve in front of his eyes.

D’Herelle next moved to chickens and was successfully able to treat fowl typhoid with a specialised phage therapy. Initially trying with the phage isolated from the soldiers, he discovered another important property of phage – they are very species specific.

Hence his French solider stools were of no use on the chickens but analysis of the chicken stools allowed him to isolate phage specific to Salmoenella gallinarum, the cause of fowl typhoid.

By 1919 d’Herelle figured he had done enough work to move to humans, only one animal trial and three years since he first found phage.

While this kind of speedy progress wouldn’t ever be allowed nowadays, d’Herelle followed all the ethical and scientific guidelines of the day.

Following the practices of the day he first tested his phage on himself his wife and children and staff at the Pasteur Institute where he worked.

The phage preparation he manufactured to treat five children suffering from dysentery seemed to work, as did his subsequent therapy for treating bubonic plague in four other patients. These successes assured him a place in history.

But as powerful as d’Herelle’s insights were his scientific method was not strong and poorly designed experiments left many wondering if what he concocted actually worked, or if he just got lucky.

His work pioneered a new wave of medical research that lasted till the late 1940’s when its position was superseded by the wonder drug penicillin.

Penicillin was very cheap, more reliable, easier to administer and perhaps most importantly was developed by more classically trained scientists compared to d’Herelle.

The influence of penicillin caused most of the world to seemingly stop considering phage therapies all at once. While the western world lost interest in the ‘invisible microbes’ the Soviet Union continued very active research.

Soviet scientists developed treatments for gastrointestinal, respiratory and wound infections and found that treatments could be made into pills, broths, injectable preparations and even mixed with creams and applied directly to open sores.

Now the biggest manufacturing operation and consumption of phage therapies occurs in Georgia in the George Eliava Institute of Bacteriophage, Microbiology and Virology, that d’Herelle co-founded with the bacteriologist George Eliava.

In more recent years an interest in phage has been renewed throughout the world. Antibiotic resistance levels in all pathogenic species are on the rise making treatment increasingly difficult.

And then there are the emerging pathogens like Acinetobacter, which possess natural resistance due to the abundance of efflux pumps – specialised structures for pumping drugs out of a bacterium.

Phage, on the other hand, have been found for almost every species of bacteria.

They often can be found in the same environment as the bacteria, moving throughout an environmental population and replicating themselves as they go.

At this stage no single definitive published clinical trial has proven safety and efficacy in humans but a wide range of currently approved veterinary medications based phage therapies are in use.

Unlike a drug, phage have evolved to be effective invaders and destroyers of bacterial cells.

Many researchers believe that this, alongside their fast replication times, might allow the treatment to evolve alongside the infectious agent, constantly adapting to any changes.

Bacteriophage are also very specific in the species and even sub-species they can invade. This allows for a more targeted approach to therapies that doesn’t result in indiscriminate killing of all bacteria, including those of use to us.

Phage also seem to be relatively non-toxic compared to current therapeutics and non-immunogenic (in some but not all cases) which means your immune system takes no notice of the phage while they are in your system.

Also unlike some existing drugs phage have been reported to cross the blood brain barrier making them a possibility to treat cases of meningitis, something many antibiotics are not suitable for.

Phage therapies are also self-limiting as phage numbers can only increase while the bacteria they can infect are there but disappear with the bacteria as they kill them off which, unlike traditional antibiotics, means you never have to worry about taking the therapeutic for the right amount of time.

But it’s not all good news for phage. The fact that phage preparations must remain refrigerated limits their usefulness at this stage as maintaining viable treatments can be difficult, particularly if we are to roll phage therapy into remote areas or the third world.

Plus, one of the major advantages of phage is also considered a drawback. The diversity of phage and the specificity in their targeting requires skilled handling of bacterial infections to quickly identify the infectious agent, sometimes to the sub-species level, before a treatment can be provided.

The point remains, however, that phage represent a major possibility for treatments of bacterial disease as we move into the future.

And while a natural progression from antibiotic therapy to the ‘next big thing’ would have been preferred, phage may be required to step up and fill a gaping hole in the management options for infectious disease while the usefulness of antibiotics reduces. Of course we might also just run out of time.

James Byrne is an assistant lecturer and a bacterial pathogenesis PhD student at the University of Adelaide.

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