
Combating multidrug-resistant bacteria with nanoengineered peptide polymers - triplesec
http://www.nature.com/articles/nmicrobiol2016162
======
danieltillett
The good thing is it works on gram negatives which we really need new
antibiotics for more than gram positives. I would be concerned how non-toxic
it in humans as peptide antibiotics have historically been pretty nasty with
lots of bad side effects.

Here is the link to the abstract [1].

1\.
[http://www.nature.com/articles/nmicrobiol2016162](http://www.nature.com/articles/nmicrobiol2016162)

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triplesec
Full title: Combating multidrug-resistant Gram-negative bacteria with
structurally nanoengineered antimicrobial peptide polymers

Media stories [http://www.sciencealert.com/the-science-world-s-freaking-
out...](http://www.sciencealert.com/the-science-world-s-freaking-out-over-
this-25-year-old-s-solution-to-antibiotic-resistance)
[http://www.telegraph.co.uk/women/health/does-this-25-year-
ol...](http://www.telegraph.co.uk/women/health/does-this-25-year-old-hold-the-
key-to-winning-the-war-against-th/)

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omginternets
This is definitely cool, but I don't see why bacteria wouldn't develop a
resistance to this as well. I have a hard time getting excited about such
things while the basic problem of reckless antibiotic use still exists.

~~~
vibrio
They will develop resistance, but that is not a reason to not do it. I fully
agree with you that reckless antibiotic use is the core problem, but public
health solutions are slow and not sexy. It reminds me that Everyone wants a
pill to treat for obesity--hundreds of millions of dollars have been spent
chasing that dragon. in reality, lifestyle choices would be more effective,
but habits like Big-Gulps and Couch-sitting die hard.

~~~
omginternets
>They will develop resistance, but that is not a reason to not do it.

Clearly. I take aspirin when I have a cold, so I have no qualms bout treating
symptoms.

I just have trouble seeing this as a meaningful step in solving the problem at
hand.

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calcrafoord
I initially read "Combining ..." and got a little bit scared

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busyant
I hate to do this since someone on another thread recently admonished HN
commenters as being like crabs that pull other crabs back down into the pot,
but I _think_ that this paper is largely PR fluff and worthy of criticism.

That being said, I am only going off of the abstract (If anyone has access to
the paper, I'd love to read it) and I'd be happy to be proven wrong about any
and all of what I say below.

ABSTRACT [w/ comments & opinions] _Here, we show that a class of antimicrobial
agents, termed ‘structurally nanoengineered antimicrobial peptide polymers’
(SNAPPs) exhibit sub-μM activity_ [if they had good MIC90 values
([http://medical-dictionary.thefreedictionary.com/MIC90](http://medical-
dictionary.thefreedictionary.com/MIC90)), they would have boasted about them.
The fact that they don't discuss MIC90 values implies that they really haven't
tested their compound against a large representative sample of Gram-
pathogens. Either that, or they have done the work and the results aren't
compelling.]

 _against all Gram-negative bacteria tested_ [My suspicion is that "all" is a
small number (see above). When I did this type of work, we routinely tested
our compounds against about 200 random hospital isolates for a _single
species._ ]

 _including ESKAPE and colistin-resistant and MDR (CMDR) pathogens, while
demonstrating low toxicity._ ["low toxicity" is a weasel phrase]

 _SNAPPs are highly effective in combating CMDR Acinetobacter baumannii
infections in vivo, the first example of a synthetic antimicrobial polymer
with CMDR Gram-negative pathogen efficacy._ [This is noteworthy only from the
standpoint that no one had previously been able to make _synthetic polymers_
with this activity.]

 _Furthermore, we did not observe any resistance acquisition by A. baumannii
(including the CMDR strain) to SNAPPs._ [This is a negative result with no
measured boundary for resistance frequency. They don't say anything like: "We
estimate that resistance to our SNAPPs is < 1e-11 per..." My suspicion is that
they ran a quick experiment or two and didn't see any resistance, but they did
not undertake a thorough analysis.]

 _Comprehensive analyses using a range of microscopy and (bio)assay techniques
revealed that the antimicrobial activity of SNAPPs proceeds via a multimodal
mechanism of bacterial cell death by outer membrane destabilization,
unregulated ion movement across the cytoplasmic membrane and induction of the
apoptotic-like death pathway,_ [The authorts want to argue that it is more
difficult for microbes to acquire resistance to SNAPPs because the SNAPPs have
multiple purported mechanism(s) of action (OM destabilization, ion gradient
destabilization, etc.). If you kill the microbe 3 different ways, then it will
be difficult for the microbe to evolve resistance against you.

There are several problems with this conclusion. First, their assays do not
pinpoint the MOA of their compound. It is possible that their compound "hits"
a _single_ target that has multiple effects on membrane stability in Gram-
negatives. If this is correct, then resistance might be trivial.

Alternatively, if they are correct, and the SNAPPs have multiple, independent
destabilizing effects on the microbial membranes, I would be concerned that
the SNAPPs would be indiscriminate enough to have an increased likelihood of
being toxic to all membranes (human included). This is speculation on my part,
however.

Finally, there is no mention of the efficacy of the SNAPPs against Gram- that
contain multi-drug resistant efflux transporters
([https://en.wikipedia.org/wiki/Efflux_(microbiology)](https://en.wikipedia.org/wiki/Efflux_\(microbiology\))).
I would be interested to know how effective SNAPPs are against these
pathogens.]

 _possibly accounting for why we did not observe resistance to SNAPPs in CMDR
bacteria._ [Again, I think they're speculating wildly based on a few negative
results.]

To me, this is a standard story that you occasionally see from academic
chemistry labs. They have an interesting compound and/or technology. They see
some antimicrobial activity with their compound and they collaborate with a
microbiology lab to demonstrate some level of efficacy.

Here, the microbiology lab is one that has been historically devoted to _oral_
microbiology
([http://findanexpert.unimelb.edu.au/display/person12757#tab-p...](http://findanexpert.unimelb.edu.au/display/person12757#tab-
publications)). My point is that neither the chemistry lab nor the oral micro
lab are really equipped to know the ins and outs of antibiotic drug
development. They are simply making a splash with the terms multi-drug-
resistance and nanoengineered.

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titzer
This will have a lot of unintended and nasty consequences. I'm going to bet on
evolution in the long run.

~~~
vibrio
I agree resistance will develop, but i can't imagine unintended and nasty
consequences. Anti-microbial peptides already exist in nature.

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nonbel
A peptide is already a polymer. This is basic definitional stuff:

>"peptides fall under the broad chemical classes of biological oligomers and
polymers"
[https://en.wikipedia.org/wiki/Peptide](https://en.wikipedia.org/wiki/Peptide)

Really the people doing the research have responsibility to speak out against
this kind of jargon loading hype... Oh I see it is the title they chose for
their own paper. I didn't read the paper, but the presence of hyping
activities meant to appeal to the lowest common denominator has proven itself
a decent heuristic so I won't bother.

Also, pretty much every bacteria is "multi-drug resistant".

~~~
VygmraMGVl
These are peptides bound to a polymer particle that is not made out of
peptides, but out of another polymer (PAMAM).

The vast majority of easily cultured bacteria have demonstrated the ability to
acquire multi-drug resistance over time, but that doesn't mean that most
bacteria that currently exist are multi-drug resistant.

~~~
nonbel
I don't see how this is a correction of what I wrote. It is completely usual
for a peptide to not only be a polymer itself, but also be attached to other
polymers:
[https://en.wikipedia.org/wiki/Glycosylation](https://en.wikipedia.org/wiki/Glycosylation)

That term is totally meaningless in the title. Similarly, the term "multi-drug
resistance" has always been about hyping up your paper. It was used until 2010
or so without any definition at all, look at all those papers:

[https://www.ncbi.nlm.nih.gov/pubmed/?term=multi+drug+resista...](https://www.ncbi.nlm.nih.gov/pubmed/?term=multi+drug+resistant)

