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I work on a research project related to better understanding bacterial resistance. Concretely, we want better tooling to search for plasmids, which are sub-geno

I work on a research project related to better understanding bacterial resistance. Concretely, we want better tooling to search for plasmids, which are sub-genomic replicants that can enchance their host (bacteria) with various abilities, most importantly for humans, antimicrobial resistance. In this study, they fail to breed resistance. Fair enough, but in the wild, bacteria will eventually obtain a new, perhaps unknown plasmid with new genes. This cannot be detected in the lab. So I'm somewhat skeptical that resistance will not crop up quickly in the wild.

Scandiravian 4y ago
I'm curious how a plasmid that provide resistance would come to be, given there's no known evolutionary pressure towards it. Could you elaborate on how you think such a thing might appear in nature?
- YawningAngel 4y ago
  Why do you think there's no evolutionary pressure towards it?
  - Scandiravian 4y ago
    I think I phrased myself poorly in my original post As mentioned in another post, current antibiotics are already produced by organisms in nature, which has made bacteria more likely to develop resistance to those antibiotics over time It's a reasonable assumption, that bacteria has evolved to be more capable of developing resistance, since having the ability for a resistance gene to a specific antibiotic to develop every X generations would provide a competitive advantage This same pressure does not exist for the class of antibiotics presented in the article, so there has been no evolutionary pressure to select for genes that could potentially develop into a mechanism for resistance
- TEP_Kim_Il_Sung 4y ago
  Bacteria with a genetic defect that fails to produce the very thing the antibiotic attacks?
  - deleted 4y ago
    [deleted]
  - op00to 4y ago
    A cell wall?
    - TEP_Kim_Il_Sung 4y ago
      Could be part of a cell wall, crippling the bacteria in question in some way, compared to its' brethren, but allowing it to survive the antibiotic.
    - TeMPOraL 4y ago
      Can't be just "a cell wall", because then your antibiotic will, true to its name, end up breaking anything with a cell wall. So an effective antibiotic of this kind will handle a particular subset of cell walls, with particular properties, so it kills the pathogens without messing the patient up too much. That "subset" and "particular properties" is exactly the terrain in which evolutionary battles are fought. There is some corner of the configuration space your antibiotic is targeting, one that is reachable by the pathogen just through random mutations. Eventually, given enough chances to try, it'll find its way there. "Doors and corners, kid. That's where they get you."
- jakobnissen 4y ago
  It's not completely clear how the antibiotic works so it's too early to tell how plasmids could counter it. But some mechanisms of antibiotic resistance are relatively unspecific, such as multidrug efflux pumps. Another mechanism could be that it arises de novo in some other bacteria, then spreads on a plasmid. In that case, resistance could happen from a very low probability event that only needs to happen in one bacteria, once, worldwide.
- TeMPOraL 4y ago
  > given there's no known evolutionary pressure towards it. There will be, once the antibiotic is put into use. And that's assuming something working roughly the same way isn't, unbeknownst to us, already present in nature, leading to countermeasures also already being present in the environment. > Could you elaborate on how you think such a thing might appear in nature? The same way everything else does - natural selection. By random chance, some bacteria will survive the antibiotic treatment. Those bacteria will get to reproduce where their neighbors won't. Now, while it's possible many of the survivors will be left unharmed because their mutations made them completely broken and not worth the antibiotic's metaphorical effort, eventually there will be a survivor that's mutated just right to resist while being able to reproduce and thrive. Its lineage may still die off, but then maybe next one's won't, and now you have a resistant strain in the wild, possibly further spreading resistance-conveying plasmids.
  - Scandiravian 4y ago
    I think your explanation of how such a resistance might occur is a bit too simplified It's a reasonable assumption that bacteria in the wild have been under pressure to increase the likelihood of developing resistance genes as an adaptation to organisms producing antibiotics in nature This is a selective pressure that has been applied for millions of years and is likely the reason for anti-biotic resistance being able to develop independently over a relatively short timespan With a synthetic class of antibiotics there would not have been a pressure to increase the likelihood of resistance genes developing against this particular class of drugs As an example, soap and surface disinfectants have been in use for a long time, but to my knowledge resistance to those compounds have not develop in bacteria, despite being used much more frequently than antibiotics
noduerme 4y ago
Total yokel question, but, while you're here, could you explain why no one has developed broad-spectrum antivirals based on something like chimeric proteins described in this paper? https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022572 https://journals.plos.org/plosone/article?id=10.1371/journal...
- 1letterunixname 4y ago
  That's virology, a completely different discipline. Virions lack mitochondria, cell walls, organelles, and an ability to reproduce on their own. There is no "broad-spectrum" antiviral because of the many more functional configurations that don't share much of a template, so they are freer to mutate more wildly. The best bet is to rapidly identify emergent vectors and characterize their DNA or RNA to develop mRNA vaccines as with COVID-19. There will be no universal "cure" to the (un)common cold, only systems for developing and deploying vaccines faster.
  - jakobnirsen 4y ago
    [flagged]
    - noduerme 4y ago
      query, why did you just start an account with the same name / one letter different from the OP to post this single comment?
  - noduerme 4y ago
    I understand the basic biological difference. The mechanism of action of the protein described in the paper, apparently successfully tested against a wide variety of unrelated viruses in mice, seems to be to unfurl itself and trigger apoptosis only in the presence of single-strand viral RNA of sufficient length. I'm asking why that hasn't been followed up on.
  - Slava_Propanei 4y ago
    [dead]
1letterunixname 4y ago
The first thing I thought of: "If it's sounds too good to be true, it probably is." The "gradient vector" wrought by the survivors of natural selection and too many happy accidents will undoubtedly find a way to try to win the unending war of entropy. How curious that we should aim to stay alive, while bacteria try to do the same. Live is a competition for energy and the holding back of entropy at the gates trying to take it from us. Unless there is some magic pixie dust that attacks bacteria and doesn't cause hearing loss, olfactory loss, vision loss, tendon rupture, or colon cancer, then the search for antibiotic and antimycotic ligands will and must continue without end.

Scandiravian 4y ago

I'm curious how a plasmid that provide resistance would come to be, given there's no known evolutionary pressure towards it. Could you elaborate on how you think such a thing might appear in nature?

YawningAngel 4y ago
Why do you think there's no evolutionary pressure towards it?
- Scandiravian 4y ago
  I think I phrased myself poorly in my original post As mentioned in another post, current antibiotics are already produced by organisms in nature, which has made bacteria more likely to develop resistance to those antibiotics over time It's a reasonable assumption, that bacteria has evolved to be more capable of developing resistance, since having the ability for a resistance gene to a specific antibiotic to develop every X generations would provide a competitive advantage This same pressure does not exist for the class of antibiotics presented in the article, so there has been no evolutionary pressure to select for genes that could potentially develop into a mechanism for resistance
TEP_Kim_Il_Sung 4y ago
Bacteria with a genetic defect that fails to produce the very thing the antibiotic attacks?
- deleted 4y ago
  [deleted]
- op00to 4y ago
  A cell wall?
  - TEP_Kim_Il_Sung 4y ago
    Could be part of a cell wall, crippling the bacteria in question in some way, compared to its' brethren, but allowing it to survive the antibiotic.
  - TeMPOraL 4y ago
    Can't be just "a cell wall", because then your antibiotic will, true to its name, end up breaking anything with a cell wall. So an effective antibiotic of this kind will handle a particular subset of cell walls, with particular properties, so it kills the pathogens without messing the patient up too much. That "subset" and "particular properties" is exactly the terrain in which evolutionary battles are fought. There is some corner of the configuration space your antibiotic is targeting, one that is reachable by the pathogen just through random mutations. Eventually, given enough chances to try, it'll find its way there. "Doors and corners, kid. That's where they get you."
jakobnissen 4y ago
It's not completely clear how the antibiotic works so it's too early to tell how plasmids could counter it. But some mechanisms of antibiotic resistance are relatively unspecific, such as multidrug efflux pumps. Another mechanism could be that it arises de novo in some other bacteria, then spreads on a plasmid. In that case, resistance could happen from a very low probability event that only needs to happen in one bacteria, once, worldwide.
TeMPOraL 4y ago
> given there's no known evolutionary pressure towards it. There will be, once the antibiotic is put into use. And that's assuming something working roughly the same way isn't, unbeknownst to us, already present in nature, leading to countermeasures also already being present in the environment. > Could you elaborate on how you think such a thing might appear in nature? The same way everything else does - natural selection. By random chance, some bacteria will survive the antibiotic treatment. Those bacteria will get to reproduce where their neighbors won't. Now, while it's possible many of the survivors will be left unharmed because their mutations made them completely broken and not worth the antibiotic's metaphorical effort, eventually there will be a survivor that's mutated just right to resist while being able to reproduce and thrive. Its lineage may still die off, but then maybe next one's won't, and now you have a resistant strain in the wild, possibly further spreading resistance-conveying plasmids.
- Scandiravian 4y ago
  I think your explanation of how such a resistance might occur is a bit too simplified It's a reasonable assumption that bacteria in the wild have been under pressure to increase the likelihood of developing resistance genes as an adaptation to organisms producing antibiotics in nature This is a selective pressure that has been applied for millions of years and is likely the reason for anti-biotic resistance being able to develop independently over a relatively short timespan With a synthetic class of antibiotics there would not have been a pressure to increase the likelihood of resistance genes developing against this particular class of drugs As an example, soap and surface disinfectants have been in use for a long time, but to my knowledge resistance to those compounds have not develop in bacteria, despite being used much more frequently than antibiotics

noduerme 4y ago

Total yokel question, but, while you're here, could you explain why no one has developed broad-spectrum antivirals based on something like chimeric proteins described in this paper? https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022572 https://journals.plos.org/plosone/article?id=10.1371/journal...

1letterunixname 4y ago
That's virology, a completely different discipline. Virions lack mitochondria, cell walls, organelles, and an ability to reproduce on their own. There is no "broad-spectrum" antiviral because of the many more functional configurations that don't share much of a template, so they are freer to mutate more wildly. The best bet is to rapidly identify emergent vectors and characterize their DNA or RNA to develop mRNA vaccines as with COVID-19. There will be no universal "cure" to the (un)common cold, only systems for developing and deploying vaccines faster.
- jakobnirsen 4y ago
  [flagged]
  - noduerme 4y ago
    query, why did you just start an account with the same name / one letter different from the OP to post this single comment?
- noduerme 4y ago
  I understand the basic biological difference. The mechanism of action of the protein described in the paper, apparently successfully tested against a wide variety of unrelated viruses in mice, seems to be to unfurl itself and trigger apoptosis only in the presence of single-strand viral RNA of sufficient length. I'm asking why that hasn't been followed up on.
- Slava_Propanei 4y ago
  [dead]

1letterunixname 4y ago

The first thing I thought of: "If it's sounds too good to be true, it probably is." The "gradient vector" wrought by the survivors of natural selection and too many happy accidents will undoubtedly find a way to try to win the unending war of entropy. How curious that we should aim to stay alive, while bacteria try to do the same. Live is a competition for energy and the holding back of entropy at the gates trying to take it from us. Unless there is some magic pixie dust that attacks bacteria and doesn't cause hearing loss, olfactory loss, vision loss, tendon rupture, or colon cancer, then the search for antibiotic and antimycotic ligands will and must continue without end.