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I believed we would face an antibiotics apocalypse, until now (theguardian.com)
165 points by RockyMcNuts on Nov 21, 2015 | hide | past | favorite | 23 comments



Does that article have a second page? I read ten paragraphs of preamble followed by two paragraphs of topic.

Anyway, it is about using a class of bacteriocidal polypeptides, called bacteriocins, to treat bacterial infections in humans.

Because we have the technology to create custom polypeptide sequences, the allure is that we could design proteinaceous binding domains that are specific for some nasty pathogen. Through combinatorial chemical methods, you can generate millions of different of different peptides, and then select for the one that binds your bacterial target. Most current antibiotics are small molecules, and although you can screen chemical libraries for some antimicrobial property, you can't make millions or billions of derivatives of some candidate small molecule like you can with a peptide polymer. This could be a breakthrough method for the rapid development of antimicrobial agents.

However, there's a downside, and that is that large molecules have a more difficult time travelling through the body, specifically through tissues that have tight junctions between cells. It seems like these bacteriocins would have to be introduced intravenously (or maybe through the respiratory system, like ricin can be) as most peptides are hydrolyzed in the stomach. Even then, peptides don't easily diffuse through the blood brain barrier. I suppose they could be applied topically to treat MRSA.


I agree the article is light on substance, but for a layperson reading it, much of that preamble is probably necessary.

Anyway, I don't think the idea is to generate completely random polypeptides. The analogy with the lego bricks sounds more like they're mixing and matching known protein domains. Proteins are made of subunits called domains, and these are relatively modular, in the sense that you can concatenate the sequences for multiple domains into a single polypeptide and reasonably often end up with a functional protein consisting of the desired domains tethered together. These are called fusion proteins. In this case, the lego analogy suggests that there is a range of domains that bind to different structures on the external surfaces of bacterial cells, and another range of domains that kill bacterial cells by different mechanisms.

So, if you want to kill species X, you first find a binding domain A that binds X cells, and then find an enzymatic domain B that can kill X cells, and create a fusion. This fusion protein AB will now attach to X cells and then kill them. If species X evolves to change its shape so that A no longer binds, you find a new binding domain C that does, and create a CB fusion, which can go on killing the evolved X cells via the same mechanism. If X evolves immunity to B's mode of action, then you find a new enzymatic domain D with another mode of action and create fusion AD. Repeat as necessary.

Obviously, the success of this method depends on how many binding and enzymatic domains are effective against a particular bacterial strain. I have no idea how many bactercins are known, but presumably there must be enough to give hope to the author of this article.


So, assuming I'm parsing you correctly, would you say that at this time, the benefit is that we can avoid the bacteria becoming resistant by creating a large range of things that it would have to become resistant to, and the down-side is that since these polypeptides are larger, they will not be as able to be administered where needed? Could this also mean that we end up treating an infection in a specific spot, but allowing it to continue to colonize a different part of the body? For instance, say, in the case of a UTI, where the infection could have moved further up the GI tract, and treatment with polypeptides would work for the urethra, but possibly not further up?


If a particular bacterial strain were to become resistant to a particular bacteriocin, we could use directed evolution methods to modify the bacteriocin.

For example, say the pathogen develops a mutation so that the bacteriocin's binding domain no longer recognizes its bacterial target. Because the bacteriocin is a class of peptide, and not a small molecule, its (theoretically) rather simple to run a directed evolution program in order to discover a variant of the original bacteriocin that will bind the mutant strain. It would be far more difficult to do the same thing with some small molecule antibiotic, and you'd never be able to generate the number of derivatives of the small molecule that you could with a peptide.

Similarly, if the bacteria develops a mutation so that the active domain of the bacteriocin no longer works properly, you can run the same sort of directed evolution experiment.

Or, you could conceivably use a different binding domain altogether as was suggested in the article and in this thread.

As for the delivery of the antibiotic, it needs some way to come in contact with the pathogen. A topical wound that is infected with some form of staphylococcus, for example, could be treated with some sort of ointment. But relying on the body's circulatory system to deliver the drug, well that would seemingly be more difficult than just taking a pill.


Bacteriophage already evolve in the way you suggest, and are typically administered topically rather than systemically.


Maybe one could synthesize analogs that don't get hydrolyzed in the stomach.


That's harder than it sounds. Insulin is a prime candidate for that - just synthesize an insulin analog that doesn't get hydrolyzed in the stomach, and you have oral insulin. It would be an instant blockbuster drug. There have been billions of dollars spent on research trying to do just that, with no success yet.


Another source of hope is phage therapy, an old Soviet branch of medicine that developed in relative obscurity:

http://www.nature.com/news/phage-therapy-gets-revitalized-1....


The problem with phage therapy is partly economic, partly regulatory, and partly practical.

Unlike antibiotics, phages are entirely natural, and so can't be patented; in a bacterial broth they multiply at an astonishing rate (about a thousandfold every hour IIRC); and they're obtained from stuff which we have so much of that a large part of our infrastructure has been built just to get rid of it (raw sewage). So there's no money to be made out of phage therapy, and it threatens whatever money pharmaceutical companies make out of selling antibiotics. So, it's no surprise they were a big success in communist countries and a failure in capitalist ones. After the fall of communism, they continue to be used in Georgia, but every attempt to make money out of them has failed.

Also, they're treated as a drug by regulatory bodies (which were established with pharmaceutical companies in mind), and so every phage strain, and every phage cocktail, would need extensive trials before approval is granted, despite their being completely safe and impossible to overdose on.

The practical reason for not using them is that antibiotics are trivial to administer compared to bacteriophage, you don't need to identify the exact strain, and antibiotics are less of a problem to store.

However, when bacteria develop resistance to a particular phage, the phage can and will evolve to kill the new strain of bacteria. Also, with phage therapy, dosage is not an issue as the phage multiplies on contact with its target bacteria. Phage doesn't mess with your gut flora. And finally, nobody is allergic to phage.

The NHS and other health services should follow Georgia's lead and develop stocks of phage (which are used at present to identify bacterial strains), as well as the expertise required to identify and administer them; fast-track them for use; and ignore any objections from pharmaceutical companies: the purpose is to cure people, not to make a profit.


Having worked in this area the problem is even worse as phage will be regulated as a biologic which is way worse than your typical small molecule drug.

I should point out that you can become allergic to phage just like anything.


Indeed, regulations will have to change before phage therapy is used. This should be done.

Re allergy: cite? It's of course possible to be allergic to other components of phage preparation, but I don't think anyone is allergic to the phages themselves. Many people are allergic to antibiotics, particularly those in the penicillin group.


While I agree the regulations should change I can't see the likes of the FDA changing anytime soon.

You can create anti-phage antibodies (here is a paper from 1933 on doing this [1], there are hundreds more) - if you can create antibodies to something then you can create an allergy to that thing.

1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2048399/pdf/brje...


Why couldn't you patent them? Viral strains have been patented. You couldn't patent the matter, but you could patent the use.

I think your comment around regulations is likely the major roadblock.


I think the issue is less that you can't legally patent them and more that because of the relatively high mutation rate in both phage and bacteria, patenting is too slow to be practically useful. Patents are good if the thing you're selling will still be useful in a year or two, but I don't think that's the case for phage therapy.


There is indeed a kind of overlap between the approach in the article and phage therapy, which is to clone the lytic enzymes present in the phages and use the purified products directly on bacteria (I worked on characterizing these things during my PhD). Actually there are some bacteriocins that are homologous to their phage equivalents, and so at a molecular level these two efforts are basically the same.

Further reading for the interested: http://www.ncbi.nlm.nih.gov/pubmed/16125935


From the article:

I – and many other researchers – did not believe they [bacteriocins] could be useful clinically because injecting a “foreign” bacterial protein into a patient is likely to induce a severe immune response that would make the antibiotic inactive. There were therefore gasps of amazement in Beijing at data presented from several animal studies showing this was not the case.

So, is this a case where the theory these experts embraced misled them for a long time so that none of them (until recently) even bothered to try bacteriocins on animals?

I mean, what was the breakthrough here, exactly -- actually trying it on animals, or something else?


It's a bit of an unclear sentence - bacteriocins are already present in humans, coming from bacteria living in our guts.

Maybe it's specifically about the group of bacteriocins he researches? He doesn't say which studies were presented in Beijing, so it's hard to check


I think the breakthrough was that a path of potential treatment was just paved...


There's a sense in which even antibiotics are beholden to globalization, same as the rest of us. No species will survive unless it can maintain some sort of formal truce with the global corporations.


A related thread of research uses bacteriocins as negative selective systems in cloning.

http://nar.oxfordjournals.org/content/early/2015/03/23/nar.g...

This is a huge and loosely explored space, but it is really important for basic research because the current selective markers (which are basically broad spectrum antibiotics) often have low efficiency. I feel silly for having read about this work and not made the connection to medicine!


Innovations in antibiotics discovery using mass-production methods like the iChip have already made potentially big discoveries: http://www.nature.com/news/promising-antibiotic-discovered-i...


Does anyone know of any good resources or papers related to bacteriocins as antibacterials? How much work has been done on developing something clinically relevant?


Such a stupid idea to publish this when the rest of the world is trying to dramatically curtail antibiotic use. This is still completely unproven as a viable strategy in people. How much is this approach going to cost anyway? So wealthy westerners can survive multi-drug resistant infections while the rest die from untreatable urinary tract infections? Such damaging hyperbole, completely missing the point, and from a scientist as well. Another win for science journalism.




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