Fighting evolution with evolution – using viruses to target drug-resistant bacteria

By Ed Yong | May 31, 2011 7:00 pm

We are losing the war against infectious bacteria. They are becoming increasingly resistant to our antibiotics, and we have few new drugs in the pipeline. Worse still, bacteria can transfer genes between each other with great ease, so if one of them evolves to resist an antibiotic, its neighbours can pick up the same ability. But Matti Jalasvuori from the University of Jyvaskyla doesn’t see this microscopic arms-dealing as a problem.  He sees it as a target.

Usually, antibiotic-resistance genes are found on rings of DNA called plasmids, which sit outside a bacterium’s main genome. Bacteria can donate these plasmids to one another, via their version of sex. The plasmids are portable adaptations – by trading them, bacteria can rapidly respond to new threats. But they aren’t without their downsides. Plasmids can sometimes attract viruses.

Bacteriophages (or “phages” for short) are viruses that infect and kill bacteria, and some of them specialise on those that carry plasmids. These bacteria may be able to resist antibiotics, but against the phages, their resistance is futile.

Scientists have known about these plasmid-hunting phages for over four decades, but Jalasvuori has only now shown that they could prove useful to us. He found that the phages can dramatically reduce the level of antibiotic resistance in colonies of bacteria, by selectively assassinating the plasmid-carriers.

Jalasvuori worked with two common gut bacteria – Escherichia coli and Salmonella enterica – both of which carried plasmids with antibiotic-resistance genes. In the absence of phages, all of the bacteria resisted antibiotics. When Jalasvuori added a phage called PRD1, that proportion fell to just 5% within 10 days.

The bacteria adapted to the phage assault by jettisoning their plasmids, and with them, their antibiotic-resistance genes. These survivors were now resistant to phages, but the vast majority of them could once again be killed by antibiotics.

The method isn’t perfect. A small proportion of the bacteria resisted both phages and antibiotics. However, Jalasvuori found that they also formed smaller colonies and had lost the ability to swap genes between one another. Their invincibility came at a substantial cost – compared to normal cells, they were hobbled eunuchs.

Targeting plasmids is a clever strategy that uses the rapid evolution of bacteria against them. Rather than coming up with new weapons in an ever-escalating arms race, Jalasvuori made it too costly for bacteria to keep their defences. It’s like tackling gun crime by penalising gun ownership rather than developing better bullet-proof vests.

However, Jalasvuori is refreshingly cautious about his work. He says, “There are a number of important caveats to these promising preliminary results.” For a start, his bacteria evolved under the threat of phages, but not antibiotics. If they had been exposed to both, there would almost certainly have been more double-resistant strains, which could have ultimately found ways of getting over their weaknesses.

On top of that, not all plasmids are the same; some could potentially hide from threatening phages, and go on to harbour resistance genes. Finally, as Jalasvuori writes, “As with all test-tube studies, the relevance to natural environments is unclear.”

It’s debatable whether this would ever lead to a practical way of dealing with drug-resistant microbes, but it’s certainly a lead. And with a problem as worrying as antibiotic resistance, every lead is an interesting one.

Reference: Jalasvuori, Friman, Nieminen, Bamford and Buckling. 2011. Bacteriophage selection against a plasmid-encoded sex-apparatus leads to the loss of antibiotic resistance plasmids. Biology Letters http://dx.doi.org/10.1098/rsbl.2011.0384

Image by Phylomon

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Comments (19)

  1. Ed, I think you’re a total and utter madman. I just wanted you to know that. Now, onto the topic……

    This is some neat research and I think it’s wise to use a more streamlined defense – namely, using things that are adapted to interacting with bacteria. I do think the wording is a bit odd. War, assault, weapons? Not sure if those are your words or those of Jalasvuori – but it seems to imply that bacteria are invaders. On the contrary, bacteria were everywhere and as you already know, many bacteria keep us alive – those in our gut and those in the soil, to name a few.

    Maybe the antibiotics would not have failed quite yet if we had had the sophistication to know that many healthy adults can fight infections on their own (and I acknowledge the risks, but still…..) and if we had used stuff like yogurt or live culture to crowd out bad bacteria from our gut instead of depending so much on killing everything in sight. Not sure if my idea is sound, but I do think we had a good thing and overuse of antibiotics or any drug is sure to leave us in this situation. Also, probiotics are being studied as an immune booster, but that seems to be underreported.

  2. @Emmy

    Pathogenic bacteria are invaders. They are bacteria that are not supposed to be living where they are. Also, probiotics are utterly useless (http://www.sciencebasedmedicine.org/index.php/probiotics/). The fact is, we get beneficial bacteria in our diet all the time because tiny amounts of feces are found in all foods. Moreover, “boosting the immune system” of someone without immunodeficiency is a) probably impossible (http://www.sciencebasedmedicine.org/index.php/boost-your-immune-system/) and b) almost certainly a bad thing were it possible (http://en.wikipedia.org/wiki/Autoimmunity).

  3. Sam

    Any worry about the viruses evolving, once they’ve eaten up the phages, and going after normal, helpful bacteria? Or is that totally impossible?

  4. Yep, I was wondering the same thing as what Sam said.

  5. It’s cool that some phages target bacteria with plasmids. It certainly opens up a new way of targeting drug-resistant bugs.

  6. Alex Ling

    I believe many phages are restricted to some extent to certain hosts, either due to the fact that only certain bacteria have a receptor for these phages or host restriction (i.e. restriction enzymes).

    Also, not all pathogenic bacteria are necessarily invaders– there are instances of normally innocuous bacteria that become pathogenic upon certain instances like ecological disruption.

  7. Chris M.

    @Jeff

    It was only last year that a paper was published about a gut flora transplant saving a woman’s life from Clostridium. It’s not totally unreasonable that probiotics could be useful, there just isn’t much evidence for it.

    http://www.nytimes.com/2010/07/13/science/13micro.html

  8. @Chris M.

    Note, though, that what they’re talking about in the NYTimes piece is a) a surgical technique that b) transplants fecal matter into someone with a c) extremely rare condition. Not yogurt, not probiotics, and certainly not a “healthy adult fighting an infection on their own.”

  9. http://en.wikipedia.org/wiki/Phage_therapy

    It’s worth noting that the use of bacteriophages to combat bacterial infections has a long history of which this is only one of the most recent branches.

  10. TheAndrewD

    Phage will never be used therapeutically beyond limited topical applications. There are too many variables in systemic delivery; compartmentalisation, neutralisation and sequestration by the immune system…. but they are brilliant!

    The most promise where they are concerned is using their anti host peptides to identify novel targets and antimicrobial molecules.

  11. @Jeff, you’re kidding, right? The website authors you point to didn’t appear to cite a single study. Unless I missed it – I didn’t bother reading carefully since it looked like such a one-sided site. Here are some abstracts from actual studies – feel free to refute the findings. It’s not as though I made this stuff up.

    http://www.jacionline.org/article/S0091-6749(97)70093-9/abstract

    http://onlinelibrary.wiley.com/doi/10.1053/jhep.2003.50048/abstract

    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)04259-8/fulltext#

    http://www.bmj.com/content/324/7350/1361.abstract

    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)13490-3/fulltext

  12. Robert S-R

    Phage therapy sounds safer to me, in the long run, than antibiotics. Phages are the sniper rifles to antibiotics’ flame-throwers. Extremely precise, much deadlier, and much more difficult to evolve an effective resistance to. And if a germ should evolve a resistance? The virus can also evolve a way to get past it.

    I, for one, welcome our new viral overlords.

  13. Hi Emmy –

    Thanks. The amount of data that probiotics can help infants against some types of immune mediated conditions is strong; especially agsinst the idea that they are ‘utterly useless’. I’d add these to the mix.

    http://www.ncbi.nlm.nih.gov/pubmed/18595980
    http://www.ncbi.nlm.nih.gov/pubmed/17208601
    http://www.ncbi.nlm.nih.gov/pubmed/19840300
    http://www.ncbi.nlm.nih.gov/pubmed/20642296
    http://www.ncbi.nlm.nih.gov/pubmed/20408346

    All of these are double blind, placebo controlled studies, btw.

    – pD

  14. @Emmy
    http://www.jacionline.org/article/S0091-6749(97)70093-9/abstract
    This one makes a very basic statistical error (multiple comparisons) that makes me wonder how it got into a peer-reviewed journal.

    http://onlinelibrary.wiley.com/doi/10.1053/jhep.2003.50048/abstract
    This one has an n of 4. Even if they got a statistically significant result, it’s meaningless.

    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)04259-8/fulltext#
    This is about the hygiene hypothesis, not “healthy adults fighting infections on their own.”

    http://www.bmj.com/content/324/7350/1361.abstract
    I should have moderated my original statement. Probiotics are utterly useless for what you are suggesting.

    http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(03)13490-3/fulltext
    Again, hygiene hypothesis.

    And @passionlessDrone, all of those are about the hygiene hypothesis, not probiotics as described by Emmy or typically used! Stop shifting the goalposts.

  15. Hi Jeff –

    The idea is, we may need to change how they are typically used.

    Regarding the hygeneine hypothesis, this study showed a decrease in gestational diabetes mellitus in pregnant mothers given probiotics.

    http://www.ncbi.nlm.nih.gov/pubmed?term=probiotics%20gestational%20diabetes%20

    Do you think this was due to the hygeine hypothesis?

    http://www.ncbi.nlm.nih.gov/pubmed/20803023 — shows a decrease in getting a cold, and the number of days sick during a cold for the control group.

    http://www.ncbi.nlm.nih.gov/pubmed/20485304 — Another blinded, placebo control study showing a reduction in sickness in children in the control group.

    So much for the notion that modifying the immune system is ‘impossible’.

    http://www.ncbi.nlm.nih.gov/pubmed/20159049 — shows an increase in killer cell count and IL-10; which is rather contrary to the idea promoted in the SBM article that an inflammatory response is the only type of immunomodulatory effect possible from probiotics.

    http://www.ncbi.nlm.nih.gov/pubmed/20735782 — Shows significant improvement in Crohn’s patients, and a transient decrease in inflammatory cytokines.

    http://www.ncbi.nlm.nih.gov/pubmed/19555446 — shows that infants given prebiotics have reduced hyperbilirubinaemia.

    Regarding goalposts, if you don’t want to defend your use of ‘utterly useless’, that means you are the one shifting the goalposts.

    – pD

  16. @Jeff fair enough, I should have been more careful with my references. I wasn’t trying to bamboozle anyone. (And I’m sure PDrone was not either).

    ;)

  17. Joman

    Phage therapy is nothing new and I recall reading how it has been used for decades in Eastern Europe as a form of personalized medicine where custom-made cultures are grown (with minimal effort) to treat particularly resistant infections.
    I also remember the article pointing out that the reason that it isn’t more widespread in the developed world is because due to the highly specialized nature of every culture that is made, that drug testing in such countries would require that you perform a full set of clinical trials for every phage grown for each patient. Furthermore as every page cocktail is unique to the infection it is made to treat, it would be meaningless i.e. unprofitable, to patent them as even the same type of infection may require a different cocktail depending on the strains and resistances present.
    Instead western research has focused on isolating the proteins/enzymes the phages use to infiltrate and infect bacterial cells in the hopes of developing a new class of drugs that can be patented but this seems like a a short-sighted approach. Phage therapy on the other hand possess the same advantage that bacteria have been using to flout antibiotic research for decades in that they can evolve ways to overcome bacterial defenses just as quickly as bacteria can evolve ways to elude them. That is far more efficient than waiting for some overworked grad student to crystallize a new protein that may or may not be a useful target for drug development.

    If the FDA is really concerned about the rise of antibiotic resistance, they should seriously consider revising regulations to be more friendly (and profitable) to this area of research.

  18. maurice

    Topical and environmental applications make some sense (and had some degree of success in Soviet Georgia).
    However, at present, I see no way that phage therapy can replace the use of systemic antibiotics in people with functioning immune systems.
    In order to get to the bacteria causing problems, the phages would need to escape our immune systems — they’ve coevolved to deal with bacterial defenses, but not mammalian ones.
    As soon as phages are in the bloodstream or tissues, they’re gonna get whacked by the innate immune response before they can do much against the bacteria

  19. Brian Too

    I have long believed that phages are a brilliant way of attacking the problem of antibiotic resistance. It’s a completely different way of approaching the treatment of infections. That’s it’s strength.

    Sure it has problems. So what? Antibiotics have problems too. That didn’t stop us from productively using them.

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