
I believed we would face an antibiotics apocalypse, until now - RockyMcNuts
http://www.theguardian.com/commentisfree/2015/nov/20/antibiotics-apocalypse-research-resistance-threat-breakthrough
======
OrthoMetaPara
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.

~~~
FungalRaincloud
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?

~~~
OrthoMetaPara
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.

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

------
nyolfen
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....](http://www.nature.com/news/phage-therapy-gets-
revitalized-1.15348)

~~~
DonaldFisk
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.

~~~
danieltillett
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.

~~~
DonaldFisk
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.

~~~
danieltillett
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...](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2048399/pdf/brjexppathol00234-0001.pdf)

------
HillaryBriss
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?

~~~
a_bonobo
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

------
erikpukinskis
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.

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

[http://nar.oxfordjournals.org/content/early/2015/03/23/nar.g...](http://nar.oxfordjournals.org/content/early/2015/03/23/nar.gkv248.short)

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!

------
DrScump
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...](http://www.nature.com/news/promising-antibiotic-discovered-
in-microbial-dark-matter-1.16675)

------
Einherji
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?

------
Gatsky
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.

