How to Kill Antibiotic-Resistant ‘Superbugs’ Without Antibiotics | Hacker News Reader

How to Kill Antibiotic-Resistant ‘Superbugs’ Without Antibiotics

edgylabs.com

85 pointsParbeyjr37 comments

Whenever i see nano particles used to combat disease, I am always interested in the off target controls. Since they are using physical mechanism to disrupt membrane stability (in the case of bacteria), controlling targeting is very difficult and requires vastly different membrane properties on the surface of bacteria vs regular cells. Issues usually involve lodging of nano particles in the liver or kidneys/ lysis and cytotoxicity . Here they looked at haemolytic and necrotic activities in cells and assessed whether the mice survived- most are short term, and aggregation of nano particles is not uncommon to cause large obvious pathology, it just takes time.

I looked up the core molecule 'PAMAM' or Poly(amidoamine) and it seems to show relatively low cytoxicity, but recent studies seem to shed some more light:

'More recently, a series of studies by Mukherjee et al.[13][14][15] have shed some light on the mechanism of PAMAM cytotoxicity, providing evidence that the dendrimers break free of their encapsulating membrane (endosome) after being absorbed by the cell, causing harm to the cell's mitochondria and eventually leading to cell death. Further elucidation of the mechanism of PAMAM cytotoxicity would help resolve the dispute as to precisely how toxic the dendrimers are.'

[0]https://en.wikipedia.org/wiki/Poly(amidoamine)#Toxicity

Have there been animal model tests of these particles?

Seems so. Results are conflicting in terms of adverse effects. But seem to show these particles cross into normal cells (neurons for example)/ some lead to death some do not.

here is a quote though from one paper in mice at high concentrations: 'There was no effect on other haematological parameters. Histopathological evaluation of dendrimer-treated groups did not reveal any abnormalities in the low- and medium-dose groups, but at a high dose level, toxicity was observed in the liver and kidney.'

http://rspa.royalsocietypublishing.org/content/466/2117/1535

http://pubs.acs.org/doi/abs/10.1021/mp300391v

https://www.ncbi.nlm.nih.gov/pubmed/27534577

Full article (illegal):

http://www.nature.com.sci-hub.ac/articles/nmicrobiol2016162

Please support Sci-Hub: https://sci-hub.ac/donate

Illegal or not depends on your jurisdiction.

Looks like they found a way to generate nanoparticles that don't damage host cells, but target bacteria more or less exclusively:

  These star nanoparticles were termed ‘structurally nanoengineered
  antimicrobial peptide polymers’ (SNAPPs). Unlike existing selfassembled
  antimicrobial macromolecules, which will dissociate to
  unimers below their critical micelle concentration, SNAPPs
  are stable unimolecular architectures up to infinite dilution. We
  demonstrate that SNAPPs exhibit superior antibacterial activity
  against a range of clinically important Gram-negative bacteria,
  possess high therapeutic indices and display selectivity towards
  pathogens over mammalian cells.

More on biocompatibility with humans:

  As a test of biocompatibility, the haemolytic activities of SNAPPs
  were investigated by incubating them with red blood cells at different
  nanoparticle concentrations. Both S16 and S32 had negligible
  haemolytic activity. Even at a very high concentration of >100 × MBC,
  the extent of haemolysis was well below 30%. Subsequently, we
  investigated the viability of two types of mammalian cells (human
  embryonic kidney cells and rat hepatoma cells) in response to SNAPPs.
  The therapeutic indices (TI) of SNAPPs ranged from 52 to 171 ,
  generally higher than the TI of colistin, which is currently being
  used as the last therapeutic option for MDR Gram-negative pathogens

Very promising stuff. Even though this was built as a treatment for gram-negative bacteria, it seems to show an effect for gram-positive bacteria, too. Equally promising is how uniformly effective SNAPPs seemed to be across several types of gram-negative bacteria.

there's no reason to think that bacteria couldn't evolve resistance to these things, too.

Vacuoles would probably be a good solution, or some means of transport back out of the cell, and both would probably be minor modifications of existing systems in bacteria. I wonder if either would increase the stress on the host as well.

bacteria don't typically have vacuoles.

You're right, my bad.

true, but the article suggests that they were not seeing evidence of emergent resistance.

Also, the mechanism of action is one which bacteria would have a very hard time learning resistance to.

I'll believe it when they make a megaplate with that stuff.

megaplate: https://player.vimeo.com/video/180908160

> true, but the article suggests that they were not seeing evidence of emergent resistance.

It's a bit early for that, isn't it? Give it a decade or two of widespread use, and then we'll see.

> Also, the mechanism of action is one which bacteria would have a very hard time learning resistance to.

That is hopeful. But how hard is "a very hard time"? It takes decades? Centuries? Or never?

It's pretty trivial to generate resistance phenotypes in a lab at much shorter time scales to detect if it's possible.

It would seem very hard as the main mechanism of action for these nano particles is electrostatic pore formations- confirmed by their mechanistic studies.

This would require evolution of the outer membrane (OM), quite a big change for a bacteria to evolve. That said it's very surprising there are so few off target effects.

To some degree there are things that are "resistance proof", in that forming resistance to them would defacto leave organisms unable to survive in the human body.

A good example is highly acid/basic environments, thermal stress, or alcohols and solvents.

Anything that can reproduce in a 50 degree C alcohol bath, for example, is going to have a tough time adapting to humans well enough to be pathogenic.

These polymers might be a similar phenomenon, but that would also imply that they're inimical to humanity too, though perhaps at a higher concentration.

Don't forget prions. They survive temperatures above 120C and also alcohol and remain infectious. (Hydrogen peroxide and alkalis seem too work, but see [1] because I really know nothing of the science of sterilization.)

[1] https://www.ncbi.nlm.nih.gov/m/pubmed/21271212/

Prions aren't alive, by the same measure asbestos is also resistant.

Prions, like viruses, reproduce when inside a host. Parasites, bacteria, fungi, viruses and prions are all types of pathogens.

Sterilization protocols need to be followed to ensure that one patients prions don't infect another surgery patient. It turns out that relatively recent concerns over transmissible spongiform encephalopathy, caused by prions, has required changes to the sterilization procedures used in hospitals.

the fact that the polymers don't kill the mammalian cells means that whatever mammalian cells do to avoid destruction can be adapted by bacterial cells for their survival.

Except that there are fundamental differences between bacterial cells and mammalian cells that we can exploit which are extremely unlikely to change.

For example, nearly all antibiotics and antifungals target cell walls - a clear distinction that mammalian cells lack.

That's not true. Antifungals target ergosterol, which is a cell membrane compound (fungal cholesterol). Also the side effects are likely due to the similarities between ergosterol and cholesterol.

Destroying diseases through biomechanical stress sounds cool. But my concern would be whether the stress increases the mutation rate. As a well-known example of another biomechanical stress that does so, consider asbestos.

I wouldn't want a treatment for my cold that could give me cancer in 20 years...

ummm. The cold is caused by a virus (rhinovirus, RSV, enterovirus, or adenovirus) not bacteria.

Please don't take antibiotics to treat viral infections. The best you can hope for is (measurable) damage to your own gut bacteria. The worst is breeding more superbugs.

The common cold is indeed caused by a virus. However colds often result in opportunistic bacterial infections, and a very large number of what people call colds are caused by bacteria.

Therefore many (though certainly not all) colds are appropriately treated with an antibiotic.

If you were 50 and had otherwise untreatable tuberculosis, the trade off might seem clearer.

And while I guess it isn't entirely understood, the dose seems to matter with asbestos (the resulting diseases are often categorized as occupational).

I know next to nothing about this stuff but is using antibiotics or the kind of treatment outlined in this article prevent our body's natural defenses from "learning" how to fight off these bacterias? Are we basically pumping our bodies full of chemicals to the point that our immune system atrophies after several generations?

No, that's not what's happening. The bacteria are evolving resistance to antibiotics.

That's not even a little bit what's happening

> antibiotics prevent our body's natural defenses from "learning" how to fight off these bacterias

Unconstrained use of antibiotics allow bacteria's natural defenses to learn how to stay alive in our bodies.

In a bit more detail:

A bacterium does a series of chemical transformations to stay alive.

An antibiotic disrupts the bacteria lifecycle by interfering with such transformations.

These transformations might be different across bacteria. As you have millions of bacteria in an individual, some might suffer smaller results from the antibiotic, and be 'not as disrupted'.

If you don't take the full dose of antibiotics, these 'not as disrupted' bacteria might survive, make you sick again. And worse: the antibiotic will have a harder time killing them.

Some of their 'children' will be more 'disruptable' then they are, some less, but the average is less 'disruptable'.

Repeat the process many times, and you get bacteria that don't die with the antibiotic :(

Nothing to do with your immune system, that creates its own kind of 'antibiotic'

Are there substances to which in order to become resistant the bactria would become vulnerable to something else.

If there are you could attack it with a coctail of two or three.

Basically they're shooting nano bullets to the bacteria and those bullets can't be stopped. But how can they deliver those nano particles only to the harmful bacteria? They should kill also the good ones.

What about gut bacteria? Is that going to be destroyed?

Why aren't phages being researched?

Does this target mitochondria too? Other bacteriocidal antibiotics apparently do so, because the structures are similar enough.

Phages are being researched. This literally comes up in every single HN thread on antibiotics, so once more, posting my "Why Phages Aren't the Answer" shortlist. Note that I love phage therapy - this is the problems as seen by someone who doesn't think it's a dead end:

Phage therapy is neat, it really is, but there are a couple major issues:

- There is no such thing as a "broad spectrum" phage. You can't do empirical treatment using phages, and there's not really "off the shelf" phage therapy - it tends to be a bespoke creation for a particular infection.

- There's some serious regulatory problems, similar to those experienced by fecal transplant treatments. We're not yet really equipped to think about handling evolving, custom microbes as a treatment. - Because of the first, it's going to require a considerable amount more lab capacity than most clinical settings currently have, and considerable delays until treatment.

- There's also some biosafety issues around phage prep, but those are easily solvable.

It's a great way to treat particularly resistant or hard to treat infections, but it's not a particularly great general solution. There's a reason it was abandoned in countries with easy access to antibiotics - they're just roundly superior in basically every respect.

Always wondered, would it possible to develop some kind of bacteria-fighting nanobot technology?

Or would that be unrealistic as of 2016?

Can it be used to kill Cancer cells?

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