16 ms·

A broad-spectrum synthetic antibiotic that does not evoke bacterial resistance

194 points by avodonosov 4y ago

PaulKeeble 4y ago
I would like to what extent "did not evoke bacterial resistance" goes to? Does this mean we have something that will kill the bacteria we typically have issues with causing Sepsis and they will never evolve to be resistant to it? Or just that its new and nothing they tested yet seems resistant to it? Any antibiotic like this I would love for them to setup an agar half treated with the antibiotic and bacteria on the fresh food side and see just how much it is going to take for it to get past this antibiotic. It feels unlikely its genuinely impossible to be 100% effective but it would be an incredible finding if that is the case.
- runnerup 4y ago
  TFA: > Mechanistic studies of COE resistance The evolution of bacterial resistance to COE2-2hexyl was analysed in S. Typhimurium and MRSA, using either serial dilution or morbidostat-based experimental evolution (see Methods). Serial dilution. No high-level COER mutants (≥50 × MIC) of either S. Typhimurium 14028 or CA-MRSA USA300 were isolated after serial dilution for 21 days; however, low-level COER mutants were recovered in both organisms (8 × MIC and 4 × MIC, respectively) (Supplementary Fig S1a; Supplementary Table S4a and b). Morbidostat. Although high-level CIPR mutants of wild-type E. coli (BW25113) were obtained after morbidostat culture for >3 days (64-128 × MIC),35 no COER mutants were observed under these conditions. Therefore, E. coli mutL (JW4128) and wild-type A. baumannii ATCC 17978 were assessed for COER mutants since both strains possess an inherently higher frequency of mutation (∼10-100-fold), resulting from deficiencies in either methyl-directed mismatch repair or the intrinsic DNA damage-inducible response, respectively.45,46 Only low-level COER mutants (2-4 × MIC) were recovered from either of these hypermutable strains, which is in marked contrast with the high-level CIPR mutants (128 × MIC) observed for A. baumannii35 (Supplementary Fig. S1b; Supplementary Table S4c–e).
  - thejohnconway 4y ago
    That’s pretty much unreadable to someone not in the field. I’ve read it three times and still don’t know the answer to the GPs question. Yes I might be stupid, but I do have a biology degree.
    - idontwantthis 4y ago
      It sounds to me like they tried to make really easy to mutate bacteria develop resistance and failed to do so.
    - aflag 4y ago
      More to it, from a layperson's point of view, that paragraph seems to contradict the headline. As they seemed to find COER mutants, albeit in low quantities, which I read as bacteria that could actually resist it? Maybe they are saying that even though there are some bacteria that can resist it, they are never actually selected? But what would the mechanism for that be?
      - someguydave 4y ago
        they recovered “low-level COER” mutants, maybe they can’t reproduce? Edit: oh MIC is “minimum inhibitory concentration” so they only saw survivors with low levels of antibiotic. Still, it seems reasonable to be skeptical, just because their tests did not find resistance does not prove it will never happen
        aflag 4y ago
        I'm not skeptical or unskeptical. I just don't understand. My guess is that there's no construction if you understand what they are saying.
  - bongoman37 4y ago
    [dead]
epgui 4y ago
Unless there's something I'm missing here, I don't see any fundamental reason why this approach should not lead to resistance one way or another. Every new drug or therapeutic approach is good news, but it's pretty much only a matter of time until resistance develops. (Biochemist)
- runnerup 4y ago
  They're not saying it won't. They're saying they tried to breed bacteria that were resistant to it and failed to do that, so it probably won't get resistance in the wild super quickly.
  - epgui 4y ago
    I understand that- I was trying to think of how a non-biochemist would interpret the significance of the article vis-a-vis its title.
- rob74 4y ago
  Well, I guess they acknowledge that in the title already: they're just saying, that it "does not evoke bacterial resistance", not that it cannot evoke bacterial resistance.
- mjg59 4y ago
  Most antibiotics are either compounds produced as defensive mechanisms by various organisms, or are synthetic derivatives of the same. That's given bacteria a huge quantity of time to evolve resistance mechanisms, and the scale of horizontal transfer of genetic material across the entire bacterial kingdom means once we started using antibiotics ourselves it was easy to select for the genes that already existed. COE2-2hexyl is predicted to be an attack vector that hasn't occurred in nature before - based on the paper, the original observation was that in an attempt to engineer compounds to permit electron transfer across bacterial membranes, but in some cases these compounds had the side effect of inhibiting bacterial growth. They iterated through various versions and found one that simultaneously killed bacteria and had no obvious toxic impact on mammalian cells. An entirely novel attack mechanism means there's been no pressure for bacteria to evolve immunity at any point, so there's unlikely to be any handy plasmids sitting out there carrying an immunity gene and just waiting to be selected for. This doesn't mean it's impossible for immunity to be developed, but the suggestion seems to be that COE2-2hexyl interferes with well-conserved complex pathways. If there were simple mutations that granted useful immunity then the experiment in which they tested multiple generations of bacteria with increased mutation rates would probably have shown that up. That implies that it's more complicated - for instance, a mutation might reduce the effectiveness of COE2-2hexyl but in doing so might also reduce the fitness of the carrier so much that it doesn't matter. A mutation in another component of the relevant pathway might compensate for that, but you're now requiring both those mutations to end up in one bacterium before there's a fitness advantage. For a sufficiently complicated and well-tuned pathway, there may be no simple set of mutations that gets you to that point - any realistic path might involve passing through a phase of significantly reduced fitness, and that might be an insurmountable hurdle. Or the only realistic way to deal with this might be to evolve an entirely new pathway, and that's definitely not going to happen overnight. You're right that it's only a matter of time until resistance develops. The question is whether that time is on the order of years, decades, centuries, or millennia. A sufficiently long window means that we don't really have to care - either we'll be able to crank out alternatives by then, or we'll be in no position to produce synthetic antibiotics anyway. (Wrote my undergrad thesis on this, but that was over 20 years ago so please assume that I'm mostly wrong)
pauljurczak 4y ago
[flagged]
- cinntaile 4y ago
  They're talking about antibiotics resistance.
- adrianN 4y ago
  You don't need a crystal ball to see that the number of cases of multiresistant infections is growing so rapidly that at the current pace the antibiotics we have will be all but useless in a couple of decades.
  - refurb 4y ago
    Its not that simple. Some rates of resistance are dropping.
  - pauljurczak 4y ago
    "couple of decades" is not imminent.
walterbell 4y ago
The WHO "Conceptual Zero Draft" pandemic treaty from the 4th WHO INB meeting in Feb 2023 has multiple sections on bacterial resistance. If this is signed by 196 countries in May 2024, there may be new funding for research. https://inb.who.int/home/inb-process https://inb.who.int/home/inb-process > In December 2021, WHO’s Member States decided at a special session of the World Health Assembly to establish an intergovernmental negotiating body (INB), representing all regions of the world, to draft and negotiate a WHO convention, agreement, or other international instrument on pandemic prevention, preparedness and response https://apps.who.int/gb/inb/pdf_files/inb4/A_INB4_3-en.pdf https://apps.who.int/gb/inb/pdf_files/inb4/A_INB4_3-en.pdf 25. Noting that antimicrobial resistance is often described as a silent pandemic and that it could be an aggravating factor during a pandemic, Article 4 14. One Health – Multisectoral and transdisciplinary actions should recognize the interconnection between people, animals, plants and their shared environment, for which a coherent, integrated and unifying approach should be strengthened and applied with an aim to sustainably balance and optimize the health of people, animals and ecosystems, including through, but not limited to, attention to the prevention of epidemics due to pathogens resistant to antimicrobial agents and zoonotic diseases. Article 9 4. Each Party should encourage non-State actors to participate in and accelerate innovative research and development for addressing novel pathogens, pathogens resistant to antimicrobial agents and emerging and re-emerging diseases with pandemic potential. Article 18 3. The Parties will identify and integrate into relevant pandemic prevention and preparedness plans interventions that address the drivers of the emergence and re-emergence of disease at the human-animal-environment interface, including but not limited to climate change, land use change, wildlife trade, desertification and antimicrobial resistance. 7. (a) implement actions to prevent pandemics from pathogens resistant to antimicrobial agents, taking into account relevant tools and guidelines, through a One Health approach, and collaborate with relevant partners, including the Quadripartite; 7. (b) foster actions at national and community levels that encompass whole-of-government and whole-of-society approaches to control zoonotic outbreaks (in wildlife and domesticated animals), including engagement of communities in surveillance that identifies zoonotic outbreaks and antimicrobial resistance at source; 7. (c) develop and implement a national One Health action plan on antimicrobial resistance that strengthens antimicrobial stewardship in the human and animal sectors, optimizes antimicrobial consumption, increases investment in, and promotes equitable and affordable access to, new medicines, diagnostic tools, vaccines and other interventions, strengthens infection prevention and control in health care settings and sanitation and biosecurity in livestock farms, and provides technical support to developing countries; 7. (d) enhance surveillance to identify and report on pathogens resistant to antimicrobial agents in humans, livestock and aquaculture that have pandemic potential, building on the existing global reporting systems;
dr_dshiv 4y ago
…yet
- bell-cot 4y ago
  Yep. IANABC (not a biochemist), but I get the sense that "evoke bacterial resistance" is a technical phrase, with meanings not obvious to lay readers.
psychphysic 4y ago
Heh usually I'm pessimistic of these things. But this could be the gasp of air we needed. Sonic drowning music still playing in my mind when I think about antibiotic resistance.
jakobnissen 4y ago
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?
Scandiravian 4y ago
If this turns out to be safe in humans, it will be amazing news Antibiotic-resistance is incredibly scary and this seems to offer a new class of antibiotics, with a potential of more variations from the class being discovered. Though in case of resistance there's obviously no guarantee that the way bacteria overcome the resistance won't work on all variations of the class
pshirshov 4y ago
About 14 years ago I've read on HN about Epimerox, a new synthetic antibiotic which does not evoke bacterial resistance. So far we don't have it. And I have no idea why. Though it looks like just a paper is not enough for optimism. A lot of good developments just don't reach the market.
- manmal 4y ago
  Maybe because of collateral damage? Mitochondria share some vulnerabilities with bacteria.
  - monocasa 4y ago
    Or something else. Hydrofluoric acid is also a broad spectrum antibiotic that I don't think has evoked a viable bacterial response. Sort of like the xkcd that reminds you that a gun also kills cancer cells in a petri dish.
    - moremetadata 4y ago
      Formaldehyde kills Anthrax a bacillus bacteria and we make Formaldehyde from folic acid and folates. Downside of Formaldehyde is it increases the chance of cancer, probably one of the main reasons smokers got lung cancer because of the Formaldehyde in tobacco. UV light reduces folates, but does increase Vitamin D and vitamin D alters gene expression. I think something like 2000+ plus genes are influenced by Vit D, most of them being immune system genes. Creatine broken down becomes creatinine which has a gram + and gram - antimicrobial effect, which probably explains why people who have 3rd degree burns experience sudden muscle loss with rhabdomyolysis, in order to keep the bacterial levels down. Never understood why bodybuilders get told to cycle their creatine intake considering the above. Anyone know? In the meantime, I'll continue increasing my alpha-linoleic acid (£136 million per kilo from sigma-aldrich) for my omega3 intake, as it increases the size of neutrophils, which store our vitamin C and make it a hostile environment for some pathogens, before some CD4 cells carryout the phagocytosis activity.
      - 4y ago
gibolt 4y ago
Yet...
RobotToaster 4y ago
We've had a solution to antibiotic resistance for a long time, phage therapy. The only problem is they are aren't broad spectrum, and much of the research is already public domain, so can't be patented.
busyant 4y ago
This is something I know a fair amount about--I've worked for two biotech startups focused on antimicrobials and my thesis was on bacterial genetics. Whenever I hear "antibiotic that doesn't evoke bacterial resistance" I think, "You just haven't looked hard enough yet. The bacteria will 'find' a way."
- avodonosov 4y ago
  Understandable doubt, but I heard that The Lancet has serious reputation and thought it would not post complete rubbish. These concerns are addressed at least to some extent in the paper. Note also, the title not necessarily means "resistance impossible", it may mean "currently no resistance, even after explicit attempts to evoke it, using methods that for other antibiotics do result in resistance". I myself am not competent to judge. You may be right in your skepticism. From the paper: > The evolution of bacterial resistance to COE2-2hexyl was analysed in S. Typhimurium and MRSA, using either serial dilution or morbidostat-based experimental evolution (see Methods). Serial dilution. No high-level COER mutants (≥50 × MIC) of either S. Typhimurium 14028 or CA-MRSA USA300 were isolated after serial dilution for 21 days; however, low-level COER mutants were recovered in both organisms (8 × MIC and 4 × MIC, respectively) (Supplementary Fig S1a; Supplementary Table S4a and b). Morbidostat. Although high-level CIPR mutants of wild-type E. coli (BW25113) were obtained after morbidostat culture for >3 days (64-128 × MIC),35 no COER mutants were observed under these conditions. Therefore, E. coli mutL (JW4128) and wild-type A. baumannii ATCC 17978 were assessed for COER mutants since both strains possess an inherently higher frequency of mutation (∼10-100-fold), resulting from deficiencies in either methyl-directed mismatch repair or the intrinsic DNA damage-inducible response, respectively.45,46 Only low-level COER mutants (2-4 × MIC) were recovered from either of these hypermutable strains, which is in marked contrast with the high-level CIPR mutants (128 × MIC) observed for A. baumannii35 (Supplementary Fig. S1b; Supplementary Table S4c–e). Whole genome sequencing of COER mutants revealed mutation(s) in genes encoding essential functions involved in membrane remodelling and secretion (Supplementary Table S4a–e). Examples include: Gram-negative secA and bamA involved in outer membrane protein biogenesis and lptD from the lipopolysaccharide translocation complex47,48; pgsA from the phosphatidylglycerol biogenesis pathway49; and Gram-positive pmtR from the cytolytic peptide toxin transporter pathway.50 Consistent with this observation, a de novo constructed S. Typhimurium secA nonsense mutant (G880∗ (GGA→TGA))—derived from COER mutant analysis from serial-dilution—showed a two-fold increase in COE resistance (Supplementary Table S4a). Taken together, these data suggest that COE2-2hexyl did not evoke significant bacterial resistance, potentially due to specific effects on essential functions involved in membrane remodelling and secretion. [... they go on in the Discussion section ...] BTW, the "serial dilution" method name sounds to me like what is illustrated by this famous video: https://www.youtube.com/watch?v=plVk4NVIUh8 https://www.youtube.com/watch?v=plVk4NVIUh8
jmyeet 4y ago
Hopefully someone will be able to answer a question I have about antiobiotic resistance. This isn't my field. My understanding is that every adaptation like resistance to families of antibiotics has a "cost" to the organism. These are genes they need to carry. "Useless" genes tend to be disappear over time. As such, if we, say, stopped using pennicilin for 20 years, when we started using it again, it would be much more effective as those adaptations would slowly be lost. Is there any truth to this? Has there been any research done on this? If true, how long would it take for such adaptations to be lost? Nevermind the practical issues with implementing such a policy. I'm just interested in the bacterial evolution side of it.
eternalban 4y ago
Nice illustration courtesy of NIH on "antimicrobial mechanisms of antibiotics": https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767362/figure/antioxidants-09-01309-f001/?report=objectonly https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767362/figure/...
andrewflnr 4y ago
If this thing works as advertised, it's going to wreck people's gut flora, right? Do we have adequate options for restoring them?
photochemsyn 4y ago
The claim regarding a low likelihood of the evolution of resistance to this compound in bacteria seems based primarily on this: > "Furthermore, no mutations were observed that affect any of the numerous efflux pumps, which were readily obtained using the same approach for ciprofloxacin resistance, suggesting that COE2-2hexyl is not an efflux pump substrate or effector. MDR [Multi-drug-resistant] pathogens whose resistance is driven primarily by pre-existing efflux upregulation would thus remain susceptible to COEs." The ability of infectious microbes to rapidly pump antibiotics out of their cells is a main feature of the rise of antibiotic resistance, and is a core element of microbial physiology: "Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants" (2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029519/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029519/ So, they're saying they see no evidence that this class of compounds is targeted by any known efflux pump protein complexes, and thus resistance by that route is unlikely to quickly develop. This however doesn't rule out other mechanisms, such as the infectious bacteria acquiring enzyme genes that allow it to cleave the molecule, etc. As far as selective pressure, one main culprit in the rise of antibiotic resistance was their use in industrial farming systems, in which animals confined side by side are given steady doses of antibiotics as a preventive measure and for growth-promotion, which results in a steady evolutionary selective pressure for mutations that conferred resistance. Widespread prescription by doctors to human patients who might have just had viral infections, and lack of enforcement of the full course of antibiotics also were at fault, but factory farming practices seem to be the main issue (note the EU banned much of this in 2006): > "Animals on U.S. factory farms consume over 80 percent of the nation’s antibiotics; a nine percent rise in the sale of antibiotics used in U.S. animal feed between 2017 and 2018 indicates that antibiotic usage by factory farms is still increasing." https://sentientmedia.org/the-indisputable-link-between-antibiotic-resistance-and-factory-farming/ https://sentientmedia.org/the-indisputable-link-between-anti...
- elil17 4y ago
  Thank you for your excellent summary. How does antibiotic resistance in animals cross over to antibiotic resistance in humans?
  - 4y ago
ActionHank 4y ago
YET
stainablesteel 4y ago
sure it doesn't i'll note these authors names so i can paint them as clowns if i ever run into them
Slava_Propanei 4y ago
[dead]
graypegg 4y ago
I wonder if “microbicidologist” will become a specialized medical profession like anesthesiologist or pharmacist. (Some procedure or knowledge that’s uniquely complex.) Feels like we’re entering an age where knowing what antibiotic to administer, for how long, and when to shelve one permanently is going to require more specialized training out of the scope of the usual GP. Could imagine hospitals separating pharmacology and microbicidology into two departments, so newer antimicrobial agents only get dispensed for severe resistant cases, and I’d imagine there’d be a lot of reporting for each case.
- foxyv 4y ago
  There is already an Infectious Disease specialization that does this exact thing.
  - graypegg 4y ago
    Ah makes sense! I’m no expert.
    - foxyv 4y ago
      Relevant YouTube video lol https://www.youtube.com/watch?v=sx7R6iS6btc https://www.youtube.com/watch?v=sx7R6iS6btc

194 points by avodonosov 4y ago

I would like to what extent "did not evoke bacterial resistance" goes to? Does this mean we have something that will kill the bacteria we typically have issues with causing Sepsis and they will never evolve to be resistant to it? Or just that its new and nothing they tested yet seems resistant to it? Any antibiotic like this I would love for them to setup an agar half treated with the antibiotic and bacteria on the fresh food side and see just how much it is going to take for it to get past this antibiotic. It feels unlikely its genuinely impossible to be 100% effective but it would be an incredible finding if that is the case.

runnerup 4y ago
TFA: > Mechanistic studies of COE resistance The evolution of bacterial resistance to COE2-2hexyl was analysed in S. Typhimurium and MRSA, using either serial dilution or morbidostat-based experimental evolution (see Methods). Serial dilution. No high-level COER mutants (≥50 × MIC) of either S. Typhimurium 14028 or CA-MRSA USA300 were isolated after serial dilution for 21 days; however, low-level COER mutants were recovered in both organisms (8 × MIC and 4 × MIC, respectively) (Supplementary Fig S1a; Supplementary Table S4a and b). Morbidostat. Although high-level CIPR mutants of wild-type E. coli (BW25113) were obtained after morbidostat culture for >3 days (64-128 × MIC),35 no COER mutants were observed under these conditions. Therefore, E. coli mutL (JW4128) and wild-type A. baumannii ATCC 17978 were assessed for COER mutants since both strains possess an inherently higher frequency of mutation (∼10-100-fold), resulting from deficiencies in either methyl-directed mismatch repair or the intrinsic DNA damage-inducible response, respectively.45,46 Only low-level COER mutants (2-4 × MIC) were recovered from either of these hypermutable strains, which is in marked contrast with the high-level CIPR mutants (128 × MIC) observed for A. baumannii35 (Supplementary Fig. S1b; Supplementary Table S4c–e).
- thejohnconway 4y ago
  That’s pretty much unreadable to someone not in the field. I’ve read it three times and still don’t know the answer to the GPs question. Yes I might be stupid, but I do have a biology degree.
  - idontwantthis 4y ago
    It sounds to me like they tried to make really easy to mutate bacteria develop resistance and failed to do so.
  - aflag 4y ago
    More to it, from a layperson's point of view, that paragraph seems to contradict the headline. As they seemed to find COER mutants, albeit in low quantities, which I read as bacteria that could actually resist it? Maybe they are saying that even though there are some bacteria that can resist it, they are never actually selected? But what would the mechanism for that be?
    - someguydave 4y ago
      they recovered “low-level COER” mutants, maybe they can’t reproduce? Edit: oh MIC is “minimum inhibitory concentration” so they only saw survivors with low levels of antibiotic. Still, it seems reasonable to be skeptical, just because their tests did not find resistance does not prove it will never happen
      - aflag 4y ago
        I'm not skeptical or unskeptical. I just don't understand. My guess is that there's no construction if you understand what they are saying.
- bongoman37 4y ago
  [dead]

epgui 4y ago

Unless there's something I'm missing here, I don't see any fundamental reason why this approach should not lead to resistance one way or another. Every new drug or therapeutic approach is good news, but it's pretty much only a matter of time until resistance develops. (Biochemist)

runnerup 4y ago
They're not saying it won't. They're saying they tried to breed bacteria that were resistant to it and failed to do that, so it probably won't get resistance in the wild super quickly.
- epgui 4y ago
  I understand that- I was trying to think of how a non-biochemist would interpret the significance of the article vis-a-vis its title.
rob74 4y ago
Well, I guess they acknowledge that in the title already: they're just saying, that it "does not evoke bacterial resistance", not that it cannot evoke bacterial resistance.
mjg59 4y ago
Most antibiotics are either compounds produced as defensive mechanisms by various organisms, or are synthetic derivatives of the same. That's given bacteria a huge quantity of time to evolve resistance mechanisms, and the scale of horizontal transfer of genetic material across the entire bacterial kingdom means once we started using antibiotics ourselves it was easy to select for the genes that already existed. COE2-2hexyl is predicted to be an attack vector that hasn't occurred in nature before - based on the paper, the original observation was that in an attempt to engineer compounds to permit electron transfer across bacterial membranes, but in some cases these compounds had the side effect of inhibiting bacterial growth. They iterated through various versions and found one that simultaneously killed bacteria and had no obvious toxic impact on mammalian cells. An entirely novel attack mechanism means there's been no pressure for bacteria to evolve immunity at any point, so there's unlikely to be any handy plasmids sitting out there carrying an immunity gene and just waiting to be selected for. This doesn't mean it's impossible for immunity to be developed, but the suggestion seems to be that COE2-2hexyl interferes with well-conserved complex pathways. If there were simple mutations that granted useful immunity then the experiment in which they tested multiple generations of bacteria with increased mutation rates would probably have shown that up. That implies that it's more complicated - for instance, a mutation might reduce the effectiveness of COE2-2hexyl but in doing so might also reduce the fitness of the carrier so much that it doesn't matter. A mutation in another component of the relevant pathway might compensate for that, but you're now requiring both those mutations to end up in one bacterium before there's a fitness advantage. For a sufficiently complicated and well-tuned pathway, there may be no simple set of mutations that gets you to that point - any realistic path might involve passing through a phase of significantly reduced fitness, and that might be an insurmountable hurdle. Or the only realistic way to deal with this might be to evolve an entirely new pathway, and that's definitely not going to happen overnight. You're right that it's only a matter of time until resistance develops. The question is whether that time is on the order of years, decades, centuries, or millennia. A sufficiently long window means that we don't really have to care - either we'll be able to crank out alternatives by then, or we'll be in no position to produce synthetic antibiotics anyway. (Wrote my undergrad thesis on this, but that was over 20 years ago so please assume that I'm mostly wrong)

pauljurczak 4y ago

[flagged]

cinntaile 4y ago
They're talking about antibiotics resistance.
adrianN 4y ago
You don't need a crystal ball to see that the number of cases of multiresistant infections is growing so rapidly that at the current pace the antibiotics we have will be all but useless in a couple of decades.
- refurb 4y ago
  Its not that simple. Some rates of resistance are dropping.
- pauljurczak 4y ago
  "couple of decades" is not imminent.

walterbell 4y ago

The WHO "Conceptual Zero Draft" pandemic treaty from the 4th WHO INB meeting in Feb 2023 has multiple sections on bacterial resistance. If this is signed by 196 countries in May 2024, there may be new funding for research. https://inb.who.int/home/inb-process https://inb.who.int/home/inb-process > In December 2021, WHO’s Member States decided at a special session of the World Health Assembly to establish an intergovernmental negotiating body (INB), representing all regions of the world, to draft and negotiate a WHO convention, agreement, or other international instrument on pandemic prevention, preparedness and response https://apps.who.int/gb/inb/pdf_files/inb4/A_INB4_3-en.pdf https://apps.who.int/gb/inb/pdf_files/inb4/A_INB4_3-en.pdf 25. Noting that antimicrobial resistance is often described as a silent pandemic and that it could be an aggravating factor during a pandemic, Article 4 14. One Health – Multisectoral and transdisciplinary actions should recognize the interconnection between people, animals, plants and their shared environment, for which a coherent, integrated and unifying approach should be strengthened and applied with an aim to sustainably balance and optimize the health of people, animals and ecosystems, including through, but not limited to, attention to the prevention of epidemics due to pathogens resistant to antimicrobial agents and zoonotic diseases. Article 9 4. Each Party should encourage non-State actors to participate in and accelerate innovative research and development for addressing novel pathogens, pathogens resistant to antimicrobial agents and emerging and re-emerging diseases with pandemic potential. Article 18 3. The Parties will identify and integrate into relevant pandemic prevention and preparedness plans interventions that address the drivers of the emergence and re-emergence of disease at the human-animal-environment interface, including but not limited to climate change, land use change, wildlife trade, desertification and antimicrobial resistance. 7. (a) implement actions to prevent pandemics from pathogens resistant to antimicrobial agents, taking into account relevant tools and guidelines, through a One Health approach, and collaborate with relevant partners, including the Quadripartite; 7. (b) foster actions at national and community levels that encompass whole-of-government and whole-of-society approaches to control zoonotic outbreaks (in wildlife and domesticated animals), including engagement of communities in surveillance that identifies zoonotic outbreaks and antimicrobial resistance at source; 7. (c) develop and implement a national One Health action plan on antimicrobial resistance that strengthens antimicrobial stewardship in the human and animal sectors, optimizes antimicrobial consumption, increases investment in, and promotes equitable and affordable access to, new medicines, diagnostic tools, vaccines and other interventions, strengthens infection prevention and control in health care settings and sanitation and biosecurity in livestock farms, and provides technical support to developing countries; 7. (d) enhance surveillance to identify and report on pathogens resistant to antimicrobial agents in humans, livestock and aquaculture that have pandemic potential, building on the existing global reporting systems;

dr_dshiv 4y ago

…yet

bell-cot 4y ago
Yep. IANABC (not a biochemist), but I get the sense that "evoke bacterial resistance" is a technical phrase, with meanings not obvious to lay readers.

psychphysic 4y ago

Heh usually I'm pessimistic of these things. But this could be the gasp of air we needed. Sonic drowning music still playing in my mind when I think about antibiotic resistance.

jakobnissen 4y ago

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?

Scandiravian 4y ago

If this turns out to be safe in humans, it will be amazing news Antibiotic-resistance is incredibly scary and this seems to offer a new class of antibiotics, with a potential of more variations from the class being discovered. Though in case of resistance there's obviously no guarantee that the way bacteria overcome the resistance won't work on all variations of the class

pshirshov 4y ago

About 14 years ago I've read on HN about Epimerox, a new synthetic antibiotic which does not evoke bacterial resistance. So far we don't have it. And I have no idea why. Though it looks like just a paper is not enough for optimism. A lot of good developments just don't reach the market.

manmal 4y ago
Maybe because of collateral damage? Mitochondria share some vulnerabilities with bacteria.
- monocasa 4y ago
  Or something else. Hydrofluoric acid is also a broad spectrum antibiotic that I don't think has evoked a viable bacterial response. Sort of like the xkcd that reminds you that a gun also kills cancer cells in a petri dish.
  - moremetadata 4y ago
    Formaldehyde kills Anthrax a bacillus bacteria and we make Formaldehyde from folic acid and folates. Downside of Formaldehyde is it increases the chance of cancer, probably one of the main reasons smokers got lung cancer because of the Formaldehyde in tobacco. UV light reduces folates, but does increase Vitamin D and vitamin D alters gene expression. I think something like 2000+ plus genes are influenced by Vit D, most of them being immune system genes. Creatine broken down becomes creatinine which has a gram + and gram - antimicrobial effect, which probably explains why people who have 3rd degree burns experience sudden muscle loss with rhabdomyolysis, in order to keep the bacterial levels down. Never understood why bodybuilders get told to cycle their creatine intake considering the above. Anyone know? In the meantime, I'll continue increasing my alpha-linoleic acid (£136 million per kilo from sigma-aldrich) for my omega3 intake, as it increases the size of neutrophils, which store our vitamin C and make it a hostile environment for some pathogens, before some CD4 cells carryout the phagocytosis activity.
    - 4y ago

gibolt 4y ago

Yet...

RobotToaster 4y ago

We've had a solution to antibiotic resistance for a long time, phage therapy. The only problem is they are aren't broad spectrum, and much of the research is already public domain, so can't be patented.

busyant 4y ago

This is something I know a fair amount about--I've worked for two biotech startups focused on antimicrobials and my thesis was on bacterial genetics. Whenever I hear "antibiotic that doesn't evoke bacterial resistance" I think, "You just haven't looked hard enough yet. The bacteria will 'find' a way."

avodonosov 4y ago
Understandable doubt, but I heard that The Lancet has serious reputation and thought it would not post complete rubbish. These concerns are addressed at least to some extent in the paper. Note also, the title not necessarily means "resistance impossible", it may mean "currently no resistance, even after explicit attempts to evoke it, using methods that for other antibiotics do result in resistance". I myself am not competent to judge. You may be right in your skepticism. From the paper: > The evolution of bacterial resistance to COE2-2hexyl was analysed in S. Typhimurium and MRSA, using either serial dilution or morbidostat-based experimental evolution (see Methods). Serial dilution. No high-level COER mutants (≥50 × MIC) of either S. Typhimurium 14028 or CA-MRSA USA300 were isolated after serial dilution for 21 days; however, low-level COER mutants were recovered in both organisms (8 × MIC and 4 × MIC, respectively) (Supplementary Fig S1a; Supplementary Table S4a and b). Morbidostat. Although high-level CIPR mutants of wild-type E. coli (BW25113) were obtained after morbidostat culture for >3 days (64-128 × MIC),35 no COER mutants were observed under these conditions. Therefore, E. coli mutL (JW4128) and wild-type A. baumannii ATCC 17978 were assessed for COER mutants since both strains possess an inherently higher frequency of mutation (∼10-100-fold), resulting from deficiencies in either methyl-directed mismatch repair or the intrinsic DNA damage-inducible response, respectively.45,46 Only low-level COER mutants (2-4 × MIC) were recovered from either of these hypermutable strains, which is in marked contrast with the high-level CIPR mutants (128 × MIC) observed for A. baumannii35 (Supplementary Fig. S1b; Supplementary Table S4c–e). Whole genome sequencing of COER mutants revealed mutation(s) in genes encoding essential functions involved in membrane remodelling and secretion (Supplementary Table S4a–e). Examples include: Gram-negative secA and bamA involved in outer membrane protein biogenesis and lptD from the lipopolysaccharide translocation complex47,48; pgsA from the phosphatidylglycerol biogenesis pathway49; and Gram-positive pmtR from the cytolytic peptide toxin transporter pathway.50 Consistent with this observation, a de novo constructed S. Typhimurium secA nonsense mutant (G880∗ (GGA→TGA))—derived from COER mutant analysis from serial-dilution—showed a two-fold increase in COE resistance (Supplementary Table S4a). Taken together, these data suggest that COE2-2hexyl did not evoke significant bacterial resistance, potentially due to specific effects on essential functions involved in membrane remodelling and secretion. [... they go on in the Discussion section ...] BTW, the "serial dilution" method name sounds to me like what is illustrated by this famous video: https://www.youtube.com/watch?v=plVk4NVIUh8 https://www.youtube.com/watch?v=plVk4NVIUh8

jmyeet 4y ago

Hopefully someone will be able to answer a question I have about antiobiotic resistance. This isn't my field. My understanding is that every adaptation like resistance to families of antibiotics has a "cost" to the organism. These are genes they need to carry. "Useless" genes tend to be disappear over time. As such, if we, say, stopped using pennicilin for 20 years, when we started using it again, it would be much more effective as those adaptations would slowly be lost. Is there any truth to this? Has there been any research done on this? If true, how long would it take for such adaptations to be lost? Nevermind the practical issues with implementing such a policy. I'm just interested in the bacterial evolution side of it.

eternalban 4y ago

Nice illustration courtesy of NIH on "antimicrobial mechanisms of antibiotics": https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767362/figure/antioxidants-09-01309-f001/?report=objectonly https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767362/figure/...

andrewflnr 4y ago

If this thing works as advertised, it's going to wreck people's gut flora, right? Do we have adequate options for restoring them?

photochemsyn 4y ago

The claim regarding a low likelihood of the evolution of resistance to this compound in bacteria seems based primarily on this: > "Furthermore, no mutations were observed that affect any of the numerous efflux pumps, which were readily obtained using the same approach for ciprofloxacin resistance, suggesting that COE2-2hexyl is not an efflux pump substrate or effector. MDR [Multi-drug-resistant] pathogens whose resistance is driven primarily by pre-existing efflux upregulation would thus remain susceptible to COEs." The ability of infectious microbes to rapidly pump antibiotics out of their cells is a main feature of the rise of antibiotic resistance, and is a core element of microbial physiology: "Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants" (2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029519/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029519/ So, they're saying they see no evidence that this class of compounds is targeted by any known efflux pump protein complexes, and thus resistance by that route is unlikely to quickly develop. This however doesn't rule out other mechanisms, such as the infectious bacteria acquiring enzyme genes that allow it to cleave the molecule, etc. As far as selective pressure, one main culprit in the rise of antibiotic resistance was their use in industrial farming systems, in which animals confined side by side are given steady doses of antibiotics as a preventive measure and for growth-promotion, which results in a steady evolutionary selective pressure for mutations that conferred resistance. Widespread prescription by doctors to human patients who might have just had viral infections, and lack of enforcement of the full course of antibiotics also were at fault, but factory farming practices seem to be the main issue (note the EU banned much of this in 2006): > "Animals on U.S. factory farms consume over 80 percent of the nation’s antibiotics; a nine percent rise in the sale of antibiotics used in U.S. animal feed between 2017 and 2018 indicates that antibiotic usage by factory farms is still increasing." https://sentientmedia.org/the-indisputable-link-between-antibiotic-resistance-and-factory-farming/ https://sentientmedia.org/the-indisputable-link-between-anti...

elil17 4y ago
Thank you for your excellent summary. How does antibiotic resistance in animals cross over to antibiotic resistance in humans?
- 4y ago

ActionHank 4y ago

YET

stainablesteel 4y ago

sure it doesn't i'll note these authors names so i can paint them as clowns if i ever run into them

Slava_Propanei 4y ago

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graypegg 4y ago

I wonder if “microbicidologist” will become a specialized medical profession like anesthesiologist or pharmacist. (Some procedure or knowledge that’s uniquely complex.) Feels like we’re entering an age where knowing what antibiotic to administer, for how long, and when to shelve one permanently is going to require more specialized training out of the scope of the usual GP. Could imagine hospitals separating pharmacology and microbicidology into two departments, so newer antimicrobial agents only get dispensed for severe resistant cases, and I’d imagine there’d be a lot of reporting for each case.

foxyv 4y ago
There is already an Infectious Disease specialization that does this exact thing.
- graypegg 4y ago
  Ah makes sense! I’m no expert.
  - foxyv 4y ago
    Relevant YouTube video lol https://www.youtube.com/watch?v=sx7R6iS6btc https://www.youtube.com/watch?v=sx7R6iS6btc