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    Ancient Bacteria-Killing Virus Holds Evolutionary Secret Against Antibiotic Resistance
    By Jennifer Wong | April 16th 2013 04:06 PM | 7 comments | Print | E-mail | Track Comments
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    My column covers the latest primary research discoveries in the life-science discipline. Much of what is reported here are considered discoveries...

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    The emergence of antibiotic-resistant bacteria is a common concern in hospitals worldwide, and is the evolutionary result of the selective pressures caused by our extensive use of antibiotics to fight bacterial infections.

    Scientists are often fighting the losing battle against antibiotic-resistant bacteria, with every new antibiotic treatment outwitted by the bacteria’s uncanny ability to adapt to whatever adversity comes their way. Although bacteria’s evasive strategies may have outwitted scientists in the last century, their strategies still fall prey to the nature’s billion-year old bacteria-killing virus known as bacteriophages.

    According to a recent PLOS One article, bacteriophages have long evolved a way to kill bacteria for good, specifically by targeting an essential and evolutionarily conserved component of any bacteria: the bacteria’s cell wall

    Why is the bacteria cell wall so important? It turns out that all bacteria have a high salt/ion content relative to their environment, attracting the influx of water through their water channels, and causing the bacteria to swell up. Much like an inflated balloon, the unabated swelling can cause the bacteria to lyse (or blow up); a process that is physically hindered by the confines of the universal cell wall found in virtually any bacterial strains throughout evolution.

    Consequently, bacteriophages have evolved to kill any bacteria by breaking down the cell wall, causing the bacteria to swell and lyse; releasing bacteriophage progeny in the process. Because the cell wall is so important for the survival of bacteria throughout evolution, it is no surprise that there are no bacterial strains in the last billion years that can resist the onslaught of bacteriophage infection.

    Exploiting nature’s wisdom to undercut bacteria’s evasive strategies, Dr. Vincent A. Fischetti at Rockefeller University and colleagues developed a new drug that suppresses the building and maintenance of the bacteria cell wall. The drug, named Epimerox,works by suppressing a key enzyme crucial for the membrane building process known as 2-epimerase; an enzyme found in virtually all bacterial strains including the methicillin (antibiotic)-resistant S. aureus (MRSA) found commonly in hospitals. Fischetti further reported that Epimerox can effectively kill MRSA, as well as a number of bacterial strains, all without causing any detectable emergence of Epimerox-resistance.

    The study suggests that Epimerox may be the first broad-acting antibiotic that can significantly reduce the probability for antibiotic-resistance.

    The discovery of Epimerox is a breakthrough in microbial control, an elixir that can help undo the evolutionary damage done by our extensive use of antibiotics in the past. 

    Schuch et al., Use of a Bacteriophage Lysin to Identify a Novel Target for Antimicrobial Development. PLOS ONE. April 2013. 10.1371/journal.pone.0060754

    Comments

    Gerhard Adam
    ... and who's going to undo the damage to all of our commensal bacteria by this use?  While I can appreciate that a life-threatening situation may require extreme actions, it's important to remember that being too aggressive with our gut bacteria is also a life-threatening condition.
    Mundus vult decipi
    jenwong
    Good point, Gerhard. I think the point you raise is a problem with all antibiotics out there. 
    You might want to read the PLOS  ONE paper, though. The authors used Epimerox injections to eliminate "bad" bacterial infection in mice. So if the drug is delivered via injection- the likelihood of it killing the "good" bacteria in the gut is probably a moot point. 
    Gerhard Adam
    I don't think it's moot, but it looks like they're targeting specific binding sites.  As a result, there will be collateral disruptions, but from what the paper suggested it appears that it was some gram-positive bacteria. 

    It wasn't more specific than that, so it's hard to tell what other organisms were involved.  They did indicate that besides B. anthracis [which was the target], it also affected S. aureus. 

    With such specificity it may actually be better than conventional antibiotics, but one can't overlook the fact that even gut bacteria may be resistant, so it's entirely dependent on the environment in which the infection occurs.  Without knowing more about how widespread the effect can be, it's hard to evaluate whether there are unintentional risks.
    Mundus vult decipi
    One of the potential beauties of using phages to attack pathogens is that most phages are highly host-specific. That is, phages will only attack E. coli or MRSA or even specific strains. So, your commensal bacteria would be unharmed. Also, when the specific target host is eliminated, the phage would be denatured, i.e., "die".

    jenwong
    While it's true that certain bacteriophages are highly host specific- there is actually evidence for broad-host range bacteriophages as well. These bacteriophages express a range of broad-acting bacteriophage lysins that can break down the cell wall of a number of bacterial species including group A streptococci, Streptococcus pneumoniae, Bacillus anthracis, Enterococcus faecalis (commensal bacteria), MRSA and Streptococcus pyogenes etc...

    Bacteriophage lysins typically recognize a region called CBD (cell-binding-domain) found in the cell wall of gram-positive bacteria. Each bacterial strain is shown to have slightly different charge in its cell wall; and so show differential susceptibility to the damaging effects of specific lysins. For instance, while PlyG lysins might work best in breaking down the cell wall S. anthracis (by cutting the PlyG receptor/CBD domain in the cell wall), the other lysin LysK can also breakdown the same cell wall albeit with less affinity.
    Lastly, the enzyme that makes the generic CBD region, 2-epimerase, is found in nearly all gram-positive bacteria, according to Fischetti. The enzyme is crucial for building the cell wall- and for supporting bacteria growth. The authors here showed that inhibition of 2-epimerase with Epimerox successfully suppressed infection by MRSA, anthrax, as well as other gram-positive and gram-negative bacteria. While Epimerox is thought to kill gram-positive bacteria by destroying the cell wall; how it kills gram-negative bacteria is still a question.

    As to whether Epimerox can kill commensal bacteria- the study shows that it does. Could this be an issue? Well- if you consider applying the drug via injection and not by ingestion- it's probably a risk worth taking to save the patient's life.
    John Hasenkam
    it is no surprise that there are no bacterial strains in the last billion years that can resist the onslaught of bacteriophage infection.

    Apoptosis: bacteria undergo a novel form of apoptosis and this probably did arise precisely because of bacteriophages. It doesn't save the single cell but it can save all the surrounding cells. 


    Cell wall hardening: In a recent fascinating little paper that re-synthesises ideas about oxidation the author puts forward the idea that oxidation is protective, this may be a protective measure which prevents bacteriophage penetration. This may represent the first evolutionary steps towards spore formation. Not sure this happens in bacteria but does in plants and animals. See: Plant cell ROS production leads to cross-linking of tyrosine-
    rich proteins in the cell wall (Bradley et al., 1992). And this ... 

    All of this leads up to some pretty conclusive evidence - in case of cell wall damage, the sigE operon is switched on. The interesting thing is, is that this isn't just a response to antibiotics either. It is highly unlikely that the system is able to respond to every different cell-wall destroying antibiotic, instead, the response is triggered by cell-wall intermediates, or degradation products that signal "Help - cell wall is being destroyed!" and switch on the sigE response, which produces proteins to mend it again.


    Oxidation: it may be damaging to bacteriophage components. 


    Cell cycle arrest or senescence: By stopping the cell cycle, shutting down genetic activity, may deprive bacteriophages of the necessary machinations to replicate. 


    Evolution is clever! 


    BTW, those clever Russkies were looking into bacteriophages decades ago. There is great promise there, something to look at, but I think you'll also find some antibiotics do function precisely by preventing cell wall formation or damaging cell wall elements. Penicillin does that. Their approach is not novel, the drug is in that it targets a different cell wall preservation process, but that is a variation on a theme, not a novelty. 




    jenwong
    Departing from what penicillin does, Epimerox suppresses 2-epimerase-mediated production of the genetric cell wall component called the CBD domain (see discussion above)- something that bacteriophages like to target. According to the authors, the CBD domain is also crucial for bacteria to multiply...

    Then why are bacteria less likely to cause resistance to Epimerox? Perhaps the answer might be because bacteriophages target CBD domains in the last billion years to kill bacteria, there might be something fundamental about CBD domains that allows it to be conserved throughout bacterial evolution. 

    But unless the paper really explains this premise further- you're right- the discovery of Epimerox is really just a new version of penicillin. But the novelty lies in the drug's ability to markedly reduce the development of antibiotic-resistant bacterial strains: an important breakthrough in this field. How Epimerox does so is unclear- and is definitely a question that merits further investigation.