7 ms·

How to Kill Antibiotic-Resistant ‘Superbugs’ Without Antibiotics

85 points by Parbeyjr 10y ago

anonymfus 10y ago
Full article (illegal): http://www.nature.com.sci-hub.ac/articles/nmicrobiol2016162 http://www.nature.com.sci-hub.ac/articles/nmicrobiol2016162 Please support Sci-Hub: https://sci-hub.ac/donate https://sci-hub.ac/donate
- Dolores12 10y ago
  Illegal or not depends on your jurisdiction.
akanet 10y ago
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.
- dnautics 10y ago
  there's no reason to think that bacteria couldn't evolve resistance to these things, too.
  - M_Grey 10y ago
    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.
    - dnautics 10y ago
      bacteria don't typically have vacuoles.
      - M_Grey 10y ago
        You're right, my bad.
  - mellavora 10y ago
    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.
    - dnautics 10y ago
      I'll believe it when they make a megaplate with that stuff. megaplate: https://player.vimeo.com/video/180908160 https://player.vimeo.com/video/180908160
    - AnimalMuppet 10y ago
      > 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?
btilly 10y ago
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...
- mellavora 10y ago
  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.
  - btilly 10y ago
    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.
- maxerickson 10y ago
  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).
sakopov 10y ago
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?
- leshow 10y ago
  No, that's not what's happening. The bacteria are evolving resistance to antibiotics.
- Fomite 10y ago
  That's not even a little bit what's happening
- fucking_tragedy 10y ago
  > 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.
  - josinalvo 10y ago
    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'
    - Senji 10y ago
Madmallard 10y ago
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.
- Fomite 10y ago
  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.
danielmorozoff 10y ago
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 https://en.wikipedia.org/wiki/Poly(amidoamine)#Toxicity
- gerbal 10y ago
  Have there been animal model tests of these particles?
  - danielmorozoff 10y ago
    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://rspa.royalsocietypublishing.org/content/466/2117/1535 http://pubs.acs.org/doi/abs/10.1021/mp300391v http://pubs.acs.org/doi/abs/10.1021/mp300391v https://www.ncbi.nlm.nih.gov/pubmed/27534577 https://www.ncbi.nlm.nih.gov/pubmed/27534577
known 10y ago
Can it be used to kill Cancer cells?
pmontra 10y ago
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.
vemv 10y ago
Always wondered, would it possible to develop some kind of bacteria-fighting nanobot technology? Or would that be unrealistic as of 2016?

85 points by Parbeyjr 10y ago

Full article (illegal): http://www.nature.com.sci-hub.ac/articles/nmicrobiol2016162 http://www.nature.com.sci-hub.ac/articles/nmicrobiol2016162 Please support Sci-Hub: https://sci-hub.ac/donate https://sci-hub.ac/donate

Dolores12 10y ago
Illegal or not depends on your jurisdiction.

akanet 10y ago

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.

dnautics 10y ago
there's no reason to think that bacteria couldn't evolve resistance to these things, too.
- M_Grey 10y ago
  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.
  - dnautics 10y ago
    bacteria don't typically have vacuoles.
    - M_Grey 10y ago
      You're right, my bad.
- mellavora 10y ago
  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.
  - dnautics 10y ago
    I'll believe it when they make a megaplate with that stuff. megaplate: https://player.vimeo.com/video/180908160 https://player.vimeo.com/video/180908160
  - AnimalMuppet 10y ago
    > 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?

btilly 10y ago

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...

mellavora 10y ago
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.
- btilly 10y ago
  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.
maxerickson 10y ago
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).

sakopov 10y ago

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?

leshow 10y ago
No, that's not what's happening. The bacteria are evolving resistance to antibiotics.
Fomite 10y ago
That's not even a little bit what's happening
fucking_tragedy 10y ago
> 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.
- josinalvo 10y ago
  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'
  - Senji 10y ago

Madmallard 10y ago

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.

Fomite 10y ago
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.

danielmorozoff 10y ago

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

gerbal 10y ago
Have there been animal model tests of these particles?
- danielmorozoff 10y ago
  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://rspa.royalsocietypublishing.org/content/466/2117/1535 http://pubs.acs.org/doi/abs/10.1021/mp300391v http://pubs.acs.org/doi/abs/10.1021/mp300391v https://www.ncbi.nlm.nih.gov/pubmed/27534577 https://www.ncbi.nlm.nih.gov/pubmed/27534577

known 10y ago

Can it be used to kill Cancer cells?

pmontra 10y ago

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.

vemv 10y ago

Always wondered, would it possible to develop some kind of bacteria-fighting nanobot technology? Or would that be unrealistic as of 2016?