Bacteriophages to Fight Bacteria: Is this the Beginning of the End?

This is the first of 6 guest posts on infectious causes of chronic disease.

By David Massaquoi

Is this the Beginning of the end of antibiotic resistant problem or just another scientific false hope of eradicating microorganisms that have co-existed with humans for millions of years? In the days before antibiotics, some researchers saw bacteriophages, viruses that can seek out and destroy bacteria, as a promising candidate for fighting infections. Now, as more organisms develop resistance to existing antibiotics, phage research is finding new favor.

(More after the jump...)

At the Society for General Microbiology meeting in Edinburgh, September, 2007, researchers presented work on incorporating bacteriophages into dressings for wounds and cleaning materials used in hospitals. According to the paper, scientists have found a way to bind the phages to polymer particles, allowing the viruses to remain active for up to three weeks rather than breaking down after a few hours. The hope is that the phage-based approach will provide new weapons in the battle against dangerous bacteria such as Methicillin-resistant Staphylococcus aureus (MRSA).

Is this the end of an era of the "superbugs" or is science hoping too much? Ever since the advancement of science in the field of microbiology, notable scientists have made "statements of hope" because of prominent discoveries in their fights against microorganisms, especially bacteria. Anytime great strides are made against these microorganisms, scientific community would hope the race against our inseparable life partners is eventually been won. With the understanding of the "germ theory" Louis Pastuer and his colleagues of those golden days of microbiology never dreamt scientist would still be fighting today to prevent and/or cure human diseases due primarily to these same bugs. When penicillin was discovered, with its successes, Alexander Fleming and colleagues could not have thought his fellow scientists would today be battling antibiotic resistant bacteria now dubbed "superbugs", even though his mentor and he warned against antibiotic resistant bacteria due to misuse of penicillin.

Successes like those made by Pastuer and colleagues of his time and the advent of penicillin and other scientific advances in the areas of infectious diseases made the then US Surgeon General, William Stewart, made the now infamous statement: "Time to close the book on infectious diseases". Today, 40years on, scientists around the globe are fighting the problems of bacteria more now than ever because of antibiotic resistant bacteria. The problems of "superbugs" have now pushed scientists to try something natural, something different, something hopeful - using virus eating bacteria to help fight bacteria infections in humans and in our environs. Is this the end of an era or the beginning of the end? Will this be another disappointment for the science community in the battle against bacteria? Margie Patlak's article for FDA, states: Book Reopened on Infectious Diseases, indirectly referring to the infamous statement of former Surgeon General, William Stewart. Is the book reopened forever or will bacteriophages help science at last to close the books on "superbugs"?

In the National Public Radio (NPR) "Science Friday" Programming, on Friday, April 4th 2008, one of the quests on the radio show stated that his research group was confident of the prospect of using bacteriophages to treat not only infected wounds or the problems of MRSA, but could also use "phage sterile sprays" in household kitchen counters to kill opportunist bacteria. "Bacteriophages, which are called bacteria 'eaters', have been around for centuries feeding on bacteria and evolving with bacteria as they change" Alexander Sulakvelidze, Vice-President, Research and Development, Chief Scientist, Intralytix, Inc, stated.

According to an article on Intralytix, Inc web, Bacteriophages were first used therapeutically in humans in 1919 (shortly after their discovery), to treat severe cases of bacteria dysentery in four children in Paris, France. According to the article, all treated patients recovered from their ailment that could have been fatal. That study, mentioned in her article was conducted in close collaboration with Felix d'Herelle, one of the discoverers of bacteriophages. Few years later, in 1921, Richard Bruynoghe and Joseph Maisin published their success of using bacteriophages to treat staphylococcal skin disease in six patients. Since that time, the idea of using phages to treat bacterial infections has been carried on around the globe.

The rapid and alarming emergence of antibiotic-resistant "superbugs" has rekindled interest in phage therapy in the West. Intralytix is developing several phage preparations for preventing and treating bacteria diseases in humans. The company's first human health product was a topical preparation, designated WPP-201â¢, for treating bacterially-infected skin ulcers commonly found in diabetic patients.

The interesting question to ask at this time is: Is this the Beginning of the end? Will the use of viruses - notably bacteria viruses that do not infect humans finally help science to solve the growing problems bacteria that has beleaguered mankind for millions of years? What if these scientifically targeted bacteria become resistance to the viruses, then what? Alexander Sulakvelidze and others on the show confidently stated that the problems of resistance to this "viral therapeutic use" should not be of concern for few reasons: First, bacteriophages are purely bacteria eating viruses and do not infect humans. The other was, these viruses are known to have evolved for billions of years with the bacteria themselves, and therefore, the viruses will evolve if the bacteria evolve to become resistant. Finally, the viral therapies will be target specific and the therapies have been successfully used before.

These are promising but ... What if these bugs becomes "super, superbugs" What if the misuse of bacteriophages caused them to evolved into something else and become human viruses? What if ...? Is this the beginning of the end? Are we finally solving the problems of "superbugs" or beginning the era of "super, superbugs". Well, it is very possible our generation will not deal with the problems of "super, superbugs" evolved from the over used of bacteriophages, after all, Fleming and his colleagues are currently not dealing with MRSA - and they warned us against misuse of penicillin. I am a very optimistic science student who hopes to someday solve the world's problem of infectious diseases, but I however asked a lot of questions - especially when I don't understand new concepts.

Originally from Sierra Leone, David has a BS degree in biology and worked at the NIH before coming to Iowa to pursue a graduate degree in public health at the Des Moines University Medical Center (DMU). He is currently enrolled at the University of Iowa in the PhD program to study Infectious Disease Epidemiology and International Health. Once he completes his studies, David hopes to engage in infectious disease research and epidemiological investigation in developing nations.

Works cited

1. Sulakvelidze, A., Alavidze, Z., and Morris, J. G., Jr., Bacteriophage therapy, Antimicrob Agents Chemother 45 (3), 649-659, 2001.

2. Bruynoghe, R. and Maisin, J., Essais de thérapeutique au moyen du bactériophage du Staphylocoque, J Compt Rend Soc Biol 85, 1120-1121, 1921.

3. Alisky, J., Iczkowski, K., Rapoport, A., and Troitsky, N., Bacteriophages show promise as antimicrobial agents, J Infect 36 (1), 5-15, 1998.

4. National Public Radio: Science Friday Programming. Friday April, 2008

5. Heist A. Human Therapeutics.

6. Patlak M. Book Reopened on Infectious Diseases. FDA Consumer magazine. April 1996.

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Very interesting. Speaking as a layman in this field, I see phages as another useful tool, not a magic bullet. Still, the more options we have in combating disease the better.

"bacteriophages", "phages" for shorthand, to fight bacteria. An interesting concept. As I understand it most, if not all, antibiotics are the natural chemical byproduct of other bacteria or fungi. These critters produce these products to protect themselves and/or to dominate an area. Sort of a microscopic chemical-biological warfare agent.

Problem is that the agents are dead. The agents do not respond to resistance developed by the other critters. Sending viruses designed to eat bacteria and making them the attacking agent could mean the viruses adapt to stay up with the bacteria. Interesting.

Of course nothing is without risk. Could the phage take up traits from the bacteria they attack? Could the bacteria, adapted to eating human tissue transfer that tendency to the virus sent to attack it?

The term "phage" also has some resonance. It has been better than a decade I think but wasn't there a science fiction TV show that featured many stories of conflict between the noble protagonists and a desperate group driven to extreme measures, harvesting of human body parts, to stay alive.

The story, as I remember it, was that these antagonists were forced to resort to these measures and become a scourge of all races around them because they were infected by a disease they called "The Phage". A sort of mega-superbug of unknown origin but one suspected of having its origin in a therapy gone wrong.

Interesting that this same language would come up as a promising therapy and the idea that there may be some greater danger should be mentioned.

Does life imitate art? An odd coincidence.

I think it would be highly unlikely that bacterial viruses could evolve into human viruses but I'd be worried that they might evolve to destroy helpful bacteria as well as harmful ones.

I must admit having a weakness for phage based antimicrobial therapy, it's one of my favorite topics. Two things to consider:

1. Regulatory issues. Phages are...weird...from a FDA approval perspective. Of the countries that routeinly use phage preperations (Georgia, the former Soviet Republic, comes to mind immediately), they are commonly formulated for a specific patient.

2. Public perception. We're injecting viruses into people to make them better. This is how at least one excellent zombie movie gets started. How happy are people going to be about that in the anti-GM, "vaccine skeptical" climate?

I am a graduate student doing evolutionary experiments with bacteriophage. I'm studying the ecological factors selecting for virulence for both the phage and bacteria. Bacteriophage are not a panacea, they are very narrow ranged, meaning that they most be targeted to specific pathogens. This can be an advantage (reduced resistance in other bugs), but also a hassle.

Also, some of the fears expressed above are unfounded. The phage have no chance at evolving to infect humans, that are far to distant for any human pathogen. Nor could they acquire pathogenicity for the bacteria they 'eat,' again the mechanisms are impossible to apply to phage biology.

The evolutionary arms race (between phage and bacteria) is an interesting idea, as both parties adapt to each other. Such a process could be put to our advantage. But, in most situations, the bacteria have the last word in becoming completely resistant, though this often comes at a cost to their growth rate.

Lastly, it has been my impression that the 'superbugs' are only described as 'super' because they are multiply antibiotic resistant, not because of any intrinsic pathogenicity. Using phage will not make the 'superbugs' more super, merely give them another hurdle they must climb.

By Josh Nahum (not verified) on 14 Apr 2008 #permalink

I don't think phages will evolve into viruses either, but there are two concerns I have. One, phage therapy could become less effective as bacteria evolve resistance. Two, the last thing we would want to do is evolve the next stx phage--the phage that causes E. coli O157:H7 to provide the toxin that makes it so dangerous. Maybe if we start using this therapy, we'll be smart about, unlike antibiotics....

Is this the beginning of the end?

I suspect not, though I'm sympathetic to the idea. There are many knock-out points to block phage infection. I doubt we'll be smart about using phage sparingly, even if it does find application. Note that the article describes a potential use in cleaning materials.

Hmmm... Unfocused treatment and continuous environmental exposure. Yeah, that should help minimize the period before treatments become ineffective.

By Unsympathetic reader (not verified) on 14 Apr 2008 #permalink

Isn't this analogous to using baculoviruses to control the insect population? I am not 100% sure of the delivery method, but weren't they fogged out into the environment to kill certain insects?

I am sure that in order to get effective spread of the baculoviruses, humans came into contact with these agents and there were no reports of anyone getting sick from them. In a way, they are safer than the horrible chemicals that are sold for pest control.

By boomer0127 (not verified) on 14 Apr 2008 #permalink

Quote:" Isn't this analogous to using baculoviruses to control the insect population? I am not 100% sure of the delivery method, but weren't they fogged out into the environment to kill certain insects?
I am sure that in order to get effective spread of the baculoviruses, humans came into contact with these agents and there were no reports of anyone getting sick from them. In a way, they are safer than the horrible chemicals that are sold for pest control."

Roughly analogous, yes.

I think it is an inevitable next step in the fight against bacteria. Once most staph and other problematic bacteria are resistant to the majority of our antibiotics, what then?

Baculoviruses are currently in use for control of insects in Europe. As for the USA, I think the USDA was using them against gypsy moths (Gyp check, a NPV). There are quite a number of baculovirus products for the control of lepidopterans.

A prime example is CpGV used for the control of the apple coddling moth (Cydia pomonella), in Germany, France.

Infestation levels of the moth can reach over 90% in untreated orchards.
NO ONE likes biting into an apple and finding half a caterpillar.

So, apple crops need to be treated, and C. pomonella develops insecticide resistance RAPIDLY. They had populations in major apple growing regions that were resistant to almost every chemical labled for use on apple.

So the use of CpGV (Cydia pomonella granulosis virus) is pretty extensive, because it is one of the few things that still works to the level required to have marketable fruit.

Plus, one can use baculoviruses for organic production, and get a higher price for the crop.

There have been no problems with humans due to the virus.

The only major problem that occured recently with CpGV is that the moth, C. pomonella, in certain isolated populations, has developed resistance to the virus, and a loss of effetive control level has occured.

The advantage of a virus, in contrast to a chemical, is one can co-adapt / co-evolve it.

My understanding is the producers of CpGV are now attempting to rear strains of CpGV that can sucessfully infect resistant hosts.

I would imagine one could easily do the same thing with bacteria.

Use a commerical bacteriophage strain against bacteria, when the bacteria populations develop resistance, breed the virus to be effective against the resistant strain.

Helping along the pathogen side of the bacterial host / viral pathogen arms race.


By Gruenhexe (not verified) on 15 Apr 2008 #permalink

Pasteur, with a vowel that sounds much like the British "er" sound.

Could the bacteria, adapted to eating human tissue transfer that tendency to the virus sent to attack it?

No, because viruses do not eat. Bacteriophages reproduce inside a bacterium, and then they destroy the bacterium's cell wall so it explodes and sets the phages free. They have no way of infecting eukaryotic cells.

I don't think phages will evolve into viruses either

They are viruses -- viruses that infect (at most a few species of) bacteria. (Or archaea. Archaeal viruses are also called phages.)

By David MarjanoviÄ (not verified) on 15 Apr 2008 #permalink

It's an interesting topic but there are too many rhetorical questions and repeats of "Is this the beginning of the end?" I found them distracting at first, then annoying.

You haven't really commented on whether bacteriophages will be significantly useful at all. Geoergia uses them on single patients, but the parctice hasn't spread. This suggests that their approach doesn't work all that well.

I'm pretty sure the reason phages were abandoned is because antibiotics have some serious advantages.
Phages are very specific, you'd need different viruses for meningococcus, syphilis and staph etc. Before resistance became a problem, penicillin would knock out all three with no trouble.
Phages are also more difficult to store and maintain. They'd need to be kept refrigerated in liquid form, not in a pill, and probably would need to be replaced more frequently.

Producing them would be easy, though.

By ericthesalmon (not verified) on 15 Apr 2008 #permalink

Yea phage! I've been talking about those in a class I'm teaching on disease, and I think they're fascinating.
ericthesalmon - if you look at the history, it seems like there were a lot of cultural reasons phage research was not picked up on in the west, mainly that the big advances in it were coming out of Soviet Georgia. And yes, in the beginning antibiotics knocked them out of the park for ease of use. But that's not the case now, not by a long shot, not given the rampant resistance to everything. I think the biggest strike against them now is the specificity, but if better diagnostics were developed to figure out which infection a person had within a day or less that problem would be gone.

if better diagnostics were developed to figure out which infection a person had within a day or less

One word: DNA.

By David Marjanović (not verified) on 16 Apr 2008 #permalink

You all talk as if bacteria cannot develop resistance to bacteriophages. Nothing could be more wrong. Bacteria and their phages have co-evolved for billions of years. If bacteria had not become resistant to phages, there would be not bacteria today!

Thankfully, bacteria have indeed developed resistance mechanisms like restriction enzymes. Worse, phages have "softened" their virulence because, like all parasites, they do not want to exterminate their host.

In brief, phages suck at curing infections. This, Carlie, is why antibiotics have been more successful than phages, not cold war politics.

This idea should work, and I hope it does. My BSc thesis was on the phages present in B.Cepacia. The main idea was that, in the USSR, at the time, antibiotics were unknown, or at least unused. What we would use antibiotics for, the Soviets would use phages for. Due to the fact that very few Soviet journals were published/translated outside the Soviet Union, the West was ignorant of the parallel use of phages. The basic idea is this: if you have 3 related bacteria, those bacteria contain phages that will 'eat' any other closely related bacteria it comes into contact with.

My main aim (at which I failed to make any conclusions) was to take various strains of B.cepacia (which causes detrimental effects on sufferers of Cystic Fibrosis, even fatality) isolate phages from non-fatal strains of B. cepacia and infect the fatal strin with them. Unfortunately, although I managed to identify and isolate the seperate strains, there seemed to be no adverse effect upon the fatal strain. I was young, inexperienced, and working under very cramped conditions (aren't we all?) but I would have been happy (if the research had gone as I expected) to provide CF sufferes with a 'phage inhaler' similar to those used by asthma sufferes, which would prevent infection by the lethal B.cepacia variant.

Here's hoping someone will take up the challenge.

I'd also be interested to know how uch of the available Russian literature has been translated.


Apologies for any typos in advance.

I heard the piece on SciFri and enjoyed it thoroughly; my question about this - and really about all viral delivery systems - is: to what extent is computer modeling being used to look for highly specific bonding sites on the surfaces of phages?

It seems to me that the possibilities for finding - pretty quickly - highly specific target sites - using structure modeling would allow for quick generation of new bacteriophages in response to new mutations.

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By William Caldwell (not verified) on 20 Aug 2011 #permalink