5 ms·

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

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
- zapdrive 4y ago
  > I heard that The Lancet has serious reputation and thought it would not post complete rubbish. After their complete u-turns on COVID origin theory and hydroxy chloroquine, I would seriously reconsider your statement.
  - elil17 4y ago
    The Lancet is a peer reviewed journal - their goal is to publish research that meets a high bar in terms of academic rigor and potential impact. They didn't take a u-turn on hydroxychloroquine, they just published multiple papers at different times that don't agree with each other.
    - pessimizer 4y ago
      They published a massive fraud that they were warned about by many. https://www.theguardian.com/world/2020/jun/10/surgisphere-sapan-desai-lancet-study-hydroxychloroquine-mass-audit-scientific-papers https://www.theguardian.com/world/2020/jun/10/surgisphere-sa... edit: more dramatic... The Lancet has made one of the biggest retractions in modern history. How could this happen? https://www.theguardian.com/commentisfree/2020/jun/05/lancet-had-to-do-one-of-the-biggest-retractions-in-modern-history-how-could-this-happen https://www.theguardian.com/commentisfree/2020/jun/05/lancet...
- outlace 4y ago
  "Lancet retracts 12-year-old article linking autism to MMR vaccines" < https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831678/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831678/ >. Even the Lancet makes big mistakes sometimes.
- busyant 4y ago
  I don't mean to bash the reputation of the Lancet nor that of the authors. But here's one thing to keep in mind with respect to this specific research. They examined the ability of two specific strains of bacteria to develop resistance. There are tons of microbial pathogens mixed together and 'promiscuously' swapping genetic material [including those for resistance] out there in the real world. Two specific strains (one for S. typhimurium and one for S. aureus) in isolation are like two water molecules in the ocean. It's a nice start, but it's far from the finish line. Also, keep in mind that the corresponding authors are academics (UCSB). The bar is pretty low with respect to what they have to deliver. I don't mean that as an insult--their job is basic research. Their job is not to make a marketed product. I used to be an "ivory tower snob." I thought university profs were a cut above industry researchers, but it's far more mixed (in my experience) and the research (between industry and academia) is judged by different metrics. In biotech, your research needs to lead to something that actually makes money. Otherwise, nobody cares. Academic research is far more exploratory, which is what I think this paper is an example of.
jvanderbot 4y ago
I've wondered about that for a while. There is some environmental cost to resistance, right? Like a bacteria strain won't necessarily proliferate resistance worldwide if we just stop using an antibiotic it reists (for long enough). If that premise is true then it should imply two things: 1. If we have "enough" "orthogonal" treatment options, we should be able to rotate on long enough time scales to avoid resistance to all treatments. Like cicadas with their prime numbered long sleep cycles. 2. Maybe we can find a treatment whose resistance is so difficult that it makes the newly resistant bacteria too vulnerable to other threats to survive in the wild, or at least at a serious disadvantage against non-resistant variants. Are these completely off base?
- Jeff_Brown 4y ago
  Rotating on a long time scale invokes a tragedy of the commons problem. You would need to get all the world's drug manufacturers to agree not to make certain products at certain times. But if small exceptions (because you know some rich person is going to get sick and hire a rogue lab to make something that's supposed to be paused) wouldn't ruin the whole scheme then it seems feasible.
  - andrewflnr 4y ago
    But there's not necessarily an advantage to breaking the rotation. The point is that the currently allowed drugs stay effective the whole time. There's a coordination problem, sure, but I don't see the incentive to hire a "rogue lab".
    - SAI_Peregrinus 4y ago
      I agree that a "rogue lab" is silly, but there is an incentive to use old stock before it goes bad but after the rotation has switched to a new drug.
      - andrewflnr 4y ago
        Eh, you can plan to allow some overlap. As long as the manufacturing is in disjoint intervals, you'll get basically the same effect.
causality0 4y ago
Right. If I recall correctly there was one lab experiment that managed to make bacteria that ignored being suspended in pure isopropanol.
- toss1 4y ago
  Yup. Similar event: A pharmacist relative who works with hospitals told me of a case where they detected excess infections, traced it to a particular operating room, then got stuck for some time before they found the source — a colony of resistant bacteria living on the spout of the antibiotic soap dispenser used by the operating team to wash hands pre-op. Another item added to the checklist.
SideburnsOfDoom 4y ago
> bacterial resistance" ... The bacteria will 'find' a way. This seems likely, to the point where I took it for granted. The fact that you know that you're in an arms race does not mean that you should stop developing new arms? Maybe the opposite. Even if the advantage gained is temporary.
shadowgovt 4y ago
Possibly, but there are a handful of synthetic compounds that aren't in the "book of life," as it were, and it would therefore be a large evolutionary leap for bacteria to develop the necessary machinery to metabolize those compounds or synthesize counter-agents. Certainly not implying it's impossible, the rate at which bacteria reproduce gives ample opportunity for mutational evolution, so relative to more complex organisms they are well positioned to develop immunities to novel synthetics. But it isn't necessarily guaranteed that the mechanism exists for it to happen.
- busyant 4y ago
  > Certainly not implying it's impossible, I agree. Never say "never." But a lot of the time, resistance is simply a matter of tinkering with target of the antibiotic (add a methyl group here and, voila! the antibiotic no longer binds effectively). Then there are multi-drug efflux pumps (https://en.wikipedia.org/wiki/Efflux_(microbiology) https://en.wikipedia.org/wiki/Efflux_(microbiology)) that "indiscriminately" toss shit out of the bacterial cell.
bilsbie 4y ago
I doubt that. Heat and alcohol are two examples that are doing just fine.
- busyant 4y ago
  > I doubt that. Heat and alcohol are two examples that are doing just fine. Yes. It's difficult to acquire resistance to heat and alcohol. The problem is that heat and alcohol are indiscriminate in their ability to kill cells, including yours and mine.
throwaway5959 4y ago
So what's the alternative? Do we accept that eventually all of our antibiotics will fail to be effective?
mattalex 4y ago
probably. But you can make it sufficiently hard: If you force the bacteria to make sufficiently large jumps in mutation to escape whatever antimicrobial you design, odds are that you force it into something either incompatible with life or make it have tradeoffs that make it easier to fight against with new drugs.

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

zapdrive 4y ago
> I heard that The Lancet has serious reputation and thought it would not post complete rubbish. After their complete u-turns on COVID origin theory and hydroxy chloroquine, I would seriously reconsider your statement.
- elil17 4y ago
  The Lancet is a peer reviewed journal - their goal is to publish research that meets a high bar in terms of academic rigor and potential impact. They didn't take a u-turn on hydroxychloroquine, they just published multiple papers at different times that don't agree with each other.
  - pessimizer 4y ago
    They published a massive fraud that they were warned about by many. https://www.theguardian.com/world/2020/jun/10/surgisphere-sapan-desai-lancet-study-hydroxychloroquine-mass-audit-scientific-papers https://www.theguardian.com/world/2020/jun/10/surgisphere-sa... edit: more dramatic... The Lancet has made one of the biggest retractions in modern history. How could this happen? https://www.theguardian.com/commentisfree/2020/jun/05/lancet-had-to-do-one-of-the-biggest-retractions-in-modern-history-how-could-this-happen https://www.theguardian.com/commentisfree/2020/jun/05/lancet...
outlace 4y ago
"Lancet retracts 12-year-old article linking autism to MMR vaccines" < https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831678/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831678/ >. Even the Lancet makes big mistakes sometimes.
busyant 4y ago
I don't mean to bash the reputation of the Lancet nor that of the authors. But here's one thing to keep in mind with respect to this specific research. They examined the ability of two specific strains of bacteria to develop resistance. There are tons of microbial pathogens mixed together and 'promiscuously' swapping genetic material [including those for resistance] out there in the real world. Two specific strains (one for S. typhimurium and one for S. aureus) in isolation are like two water molecules in the ocean. It's a nice start, but it's far from the finish line. Also, keep in mind that the corresponding authors are academics (UCSB). The bar is pretty low with respect to what they have to deliver. I don't mean that as an insult--their job is basic research. Their job is not to make a marketed product. I used to be an "ivory tower snob." I thought university profs were a cut above industry researchers, but it's far more mixed (in my experience) and the research (between industry and academia) is judged by different metrics. In biotech, your research needs to lead to something that actually makes money. Otherwise, nobody cares. Academic research is far more exploratory, which is what I think this paper is an example of.

jvanderbot 4y ago

I've wondered about that for a while. There is some environmental cost to resistance, right? Like a bacteria strain won't necessarily proliferate resistance worldwide if we just stop using an antibiotic it reists (for long enough). If that premise is true then it should imply two things: 1. If we have "enough" "orthogonal" treatment options, we should be able to rotate on long enough time scales to avoid resistance to all treatments. Like cicadas with their prime numbered long sleep cycles. 2. Maybe we can find a treatment whose resistance is so difficult that it makes the newly resistant bacteria too vulnerable to other threats to survive in the wild, or at least at a serious disadvantage against non-resistant variants. Are these completely off base?

Jeff_Brown 4y ago
Rotating on a long time scale invokes a tragedy of the commons problem. You would need to get all the world's drug manufacturers to agree not to make certain products at certain times. But if small exceptions (because you know some rich person is going to get sick and hire a rogue lab to make something that's supposed to be paused) wouldn't ruin the whole scheme then it seems feasible.
- andrewflnr 4y ago
  But there's not necessarily an advantage to breaking the rotation. The point is that the currently allowed drugs stay effective the whole time. There's a coordination problem, sure, but I don't see the incentive to hire a "rogue lab".
  - SAI_Peregrinus 4y ago
    I agree that a "rogue lab" is silly, but there is an incentive to use old stock before it goes bad but after the rotation has switched to a new drug.
    - andrewflnr 4y ago
      Eh, you can plan to allow some overlap. As long as the manufacturing is in disjoint intervals, you'll get basically the same effect.

causality0 4y ago

Right. If I recall correctly there was one lab experiment that managed to make bacteria that ignored being suspended in pure isopropanol.

toss1 4y ago
Yup. Similar event: A pharmacist relative who works with hospitals told me of a case where they detected excess infections, traced it to a particular operating room, then got stuck for some time before they found the source — a colony of resistant bacteria living on the spout of the antibiotic soap dispenser used by the operating team to wash hands pre-op. Another item added to the checklist.

SideburnsOfDoom 4y ago

> bacterial resistance" ... The bacteria will 'find' a way. This seems likely, to the point where I took it for granted. The fact that you know that you're in an arms race does not mean that you should stop developing new arms? Maybe the opposite. Even if the advantage gained is temporary.

shadowgovt 4y ago

Possibly, but there are a handful of synthetic compounds that aren't in the "book of life," as it were, and it would therefore be a large evolutionary leap for bacteria to develop the necessary machinery to metabolize those compounds or synthesize counter-agents. Certainly not implying it's impossible, the rate at which bacteria reproduce gives ample opportunity for mutational evolution, so relative to more complex organisms they are well positioned to develop immunities to novel synthetics. But it isn't necessarily guaranteed that the mechanism exists for it to happen.

busyant 4y ago
> Certainly not implying it's impossible, I agree. Never say "never." But a lot of the time, resistance is simply a matter of tinkering with target of the antibiotic (add a methyl group here and, voila! the antibiotic no longer binds effectively). Then there are multi-drug efflux pumps (https://en.wikipedia.org/wiki/Efflux_(microbiology) https://en.wikipedia.org/wiki/Efflux_(microbiology)) that "indiscriminately" toss shit out of the bacterial cell.

bilsbie 4y ago

I doubt that. Heat and alcohol are two examples that are doing just fine.

busyant 4y ago
> I doubt that. Heat and alcohol are two examples that are doing just fine. Yes. It's difficult to acquire resistance to heat and alcohol. The problem is that heat and alcohol are indiscriminate in their ability to kill cells, including yours and mine.

throwaway5959 4y ago

So what's the alternative? Do we accept that eventually all of our antibiotics will fail to be effective?

mattalex 4y ago

probably. But you can make it sufficiently hard: If you force the bacteria to make sufficiently large jumps in mutation to escape whatever antimicrobial you design, odds are that you force it into something either incompatible with life or make it have tradeoffs that make it easier to fight against with new drugs.