[HN Gopher] A broad-spectrum synthetic antibiotic that does not ...
___________________________________________________________________
A broad-spectrum synthetic antibiotic that does not evoke bacterial
resistance
Author : avodonosov
Score : 180 points
Date : 2023-02-20 03:54 UTC (19 hours ago)
(HTM) web link (www.thelancet.com)
(TXT) w3m dump (www.thelancet.com)
| gibolt wrote:
| Yet...
| stainablesteel wrote:
| sure it doesn't
|
| i'll note these authors names so i can paint them as clowns if i
| ever run into them
| ActionHank wrote:
| YET
| andrewflnr wrote:
| If this thing works as advertised, it's going to wreck people's
| gut flora, right? Do we have adequate options for restoring them?
| dr_dshiv wrote:
| ...yet
| bell-cot wrote:
| 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.
| RobotToaster wrote:
| 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.
| jakobnissen wrote:
| 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.
| noduerme wrote:
| 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...
| 1letterunixname wrote:
| 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.
| Slava_Propanei wrote:
| [dead]
| jakobnirsen wrote:
| [flagged]
| noduerme wrote:
| query, why did you just start an account with the same
| name / one letter different from the OP to post this
| single comment?
| noduerme wrote:
| 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.
| 1letterunixname wrote:
| 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 wrote:
| 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?
| TeMPOraL wrote:
| > _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 wrote:
| 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
| YawningAngel wrote:
| Why do you think there's no evolutionary pressure towards it?
| Scandiravian wrote:
| 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
| jakobnissen wrote:
| 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.
| TEP_Kim_Il_Sung wrote:
| Bacteria with a genetic defect that fails to produce the very
| thing the antibiotic attacks?
| [deleted]
| op00to wrote:
| A cell wall?
| TEP_Kim_Il_Sung wrote:
| 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 wrote:
| 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."
| PaulKeeble wrote:
| 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 wrote:
| 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 x
| 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 x MIC and 4 x
| 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 x 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 x MIC) were recovered from
| either of these hypermutable strains, which is in marked
| contrast with the high-level CIPR mutants (128 x MIC) observed
| for A. baumannii35 (Supplementary Fig. S1b; Supplementary Table
| S4c-e).
| thejohnconway wrote:
| 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 wrote:
| It sounds to me like they tried to make really easy to
| mutate bacteria develop resistance and failed to do so.
| aflag wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| [dead]
| Scandiravian wrote:
| 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
| epgui wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| 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)
| kurthr wrote:
| If only there was a small financial advantage to running
| serial dilution tests in millions of tightly packed infected
| cattle... alternatively, we can save money by dumping
| manufacturing byproducts in the Ganges.
|
| Glad we're finding new mechanisms, and hope this one stays
| effective a while.
| walterbell wrote:
| 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
|
| _> 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
| 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;
| barry-cotter wrote:
| > If this is signed by 196 countries in May 2024, there may be
| new funding for research.
|
| Significant new funding? To a first approximation new drug
| development is funded by the US because they don't have price
| controls on drugs so there are large profits to be made. To a
| second approximation by the G7 and EU since they do high impact
| research. Outside the G20 there's just not enough resources in
| terms of GDP to make a meaningful impact.
| walterbell wrote:
| If all countries are mandated to follow new WHO policy,
| that's a large market to justify funding increases by the
| research-oriented countries.
| barry-cotter wrote:
| How are the WHO going to mandate anyone to do anything? To
| paraphrase a great monster "How many legions has the UN?"
| walterbell wrote:
| That's an excellent question.
|
| The draft text above is for a new treaty, so in theory
| every country signing the treaty would be agreeing to
| enforce the provisions, since they would have spent
| 2021-2024 negotiating for the treaty to meet their goals.
| In theory, each country would enact national legislation
| to enforce the terms of the treaty. The WHO INB website
| has videos of the meetings, where you can see the health
| ministers of every country participating in the process.
|
| More problematic are the proposed WHO amendments to the
| 2005 International Health Regulations, which are to be
| voted upon in May 2023, need only a majority to pass, and
| allegedly will not require national legislation/debate by
| the 196 countries which have implemented IHR. The report
| of the review committee includes their reaction to the
| removal of IHR text on human rights, along with other
| concerns, https://apps.who.int/gb/wgihr/pdf_files/wgihr2/
| A_WGIHR2_5-en...
|
| _> The Committee strongly recommends the retention of
| the existing text "full respect for the dignity, human
| rights and fundamental freedoms of persons" as an
| overarching principle in the first paragraph, and notes
| that the concepts of human rights, dignity and
| fundamental freedoms are clearly defined within the
| framework of treaties to which many of the States Parties
| to the Regulations have adhered._
|
| While enforcement is yet unknown, contracts usually have
| consequences.
| busyant wrote:
| 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."
| shadowgovt wrote:
| 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 wrote:
| > 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)) that
| "indiscriminately" toss shit out of the bacterial cell.
| bilsbie wrote:
| I doubt that. Heat and alcohol are two examples that are doing
| just fine.
| causality0 wrote:
| Right. If I recall correctly there was one lab experiment that
| managed to make bacteria that ignored being suspended in pure
| isopropanol.
| toss1 wrote:
| 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 wrote:
| > 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.
| avodonosov wrote:
| 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 x
| 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 x MIC and 4 x
| 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 x 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 x MIC) were recovered from
| either of these hypermutable strains, which is in marked
| contrast with the high-level CIPR mutants (128 x 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
| outlace wrote:
| "Lancet retracts 12-year-old article linking autism to MMR
| vaccines" <
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831678/ >. Even
| the Lancet makes big mistakes sometimes.
| busyant wrote:
| 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.
| zapdrive wrote:
| > 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 wrote:
| 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 wrote:
| They published a massive fraud that they were warned
| about by many.
|
| 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/lan
| cet...
| jvanderbot wrote:
| 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?
| busyant wrote:
| > 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.
|
| This is something that has crossed my mind in the past. We
| rotate antibiotics in a logical fashion, in a manner similar
| to the way we rotate crops.
|
| But as someone else responded more eloquently, you're gonna
| have a hard time telling grandma's family that the most
| effective antibiotic is currently "out of rotation." And
| honestly, I'd be pretty upset if it were my grandma, too.
| sergiosgc wrote:
| That's a user interface problem. Just tie a brand to
| "whatever antibiotic is on rotation now". Grandma gets used
| to Activir, but Activir changes active principle every
| couple of years.
| Jeff_Brown wrote:
| 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.
| elil17 wrote:
| If you have enough antibiotics, there won't be an incentive
| to do that because, when someone has an antibiotic
| resistant disease, that will just mean it's time to shelve
| an old antibiotic and start using one that has been out of
| circulation for a while (e.g., no bribes/rouge labs
| required - just a call to the WHO).
|
| If you do not actually have enough antibiotics to cycle
| through, then yeah, it would not really work.
| [deleted]
| andrewflnr wrote:
| 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 wrote:
| 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 wrote:
| Eh, you can plan to allow some overlap. As long as the
| manufacturing is in disjoint intervals, you'll get
| basically the same effect.
| jcampbell1 wrote:
| The concept of a "hospital acquired infection" is a drug
| resistant infection that came from the human petri dishes
| living in the hospitals taking antibiotics and breeding
| resistant strains which don't survive in the wild.
|
| So, yes you have the right idea. There is a general push to
| not do outpatient procedures in hospitals for this very
| reason.
| eternalban wrote:
| Nice illustration courtesy of NIH on "antimicrobial mechanisms of
| antibiotics":
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767362/figure/...
| pshirshov wrote:
| 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.
| maxerickson wrote:
| The approach is advancing through human clinical trials (it
| might be the same molecule, I'm not sure).
|
| https://www.contrafect.com/pipeline/exebacase
| Varloom wrote:
| If it does not invoke bacterial resistance, its most likely
| less specific to the bacteria and can harm human cells.
|
| (think bleach, kills bacteria and there is no resistance, but
| also damage regular human cells)
| pshirshov wrote:
| Well, from what I can remember, the claims were that Epimerox
| targets a very specific protein which human cells does not
| have. Also it was claimed that said protein is very sensitive
| to conformations and stops working even after very little
| modifications.
|
| https://en.m.wikipedia.org/wiki/Epimerox
| eternalban wrote:
| https://hn.algolia.com/?dateRange=all&page=0&prefix=false&q
| u...
|
| That's all hn has had on the topic (includes yours). A
| comment mentions in passing that it is not yet used "for
| various reasons".
| manmal wrote:
| Maybe because of collateral damage? Mitochondria share some
| vulnerabilities with bacteria.
| monocasa wrote:
| 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 wrote:
| 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 (PS136 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.
| meindnoch wrote:
| Wew... So many wrong theories and half-truths here...
|
| 1. Lung cancer in smokers is not primarily caused by
| formaldehyde. There are lots of other
| irritants/carcinogens in tobacco smoke, chronic exposure
| of which contributes to cancer. Non-smokers are exposed
| to formaldehyde in comparable quantities to smokers from
| various industrial processes, household solvents, etc.
|
| 2. Rhabdomyolysis in burn victims is caused by the
| reperfusion of massively damaged muscle tissue.
|
| 3. The breakdown of muscle tissue in rhabdomyolysis
| releases creatine kinase, not creatinine.
|
| 4. Creatinine does not have antimicrobial effect at
| concentrations available in the human body. You would
| need to increase its plasma concentration 100-fold to get
| an appreciable effect on microbes. Suffice to say, that
| would be quite unhealthy for your kidneys.
|
| Where did you get these ideas from? r/nootropics?
| moremetadata wrote:
| 1. Chronic Exposure, a term that fails to quantify with
| units of measure, but it sounds psychologically shocking,
| to the point the elevated stress hormones conveniently
| not measured by so called medical experts, might start
| impeding the neutrophil functionality in turn impairing
| the wider immune system. Probably explains why the saying
| Ignorance is Bliss exists.
|
| 2. Reperfusion. Damage that occurs after blood supply is
| restored to a tissue or organ after a period of ischemia.
| Ischemia, a condition in which blood flow (and thus
| oxygen) is restricted or reduced in a part of the body. I
| guess someone had to get a leg of lamb and pump some
| blood around it whilst cooking it in order to demonstrate
| the restriction of the blood?
|
| 3.Anerobic exercise elevates creatine kinase as a marker
| of exercise. The supplementation of creatine can not be
| differentiated in kidney function tests, which are used
| by medical experts.
|
| 4.Neither do neutrophils or immune cells in general. >You
| would need to increase its plasma concentration 100-fold
| to get an appreciable effect on microbes. Why would it be
| unhealthy for your kidneys again?
|
| Where did you get these half baked theories and ideas
| from University or med school? You are certainly not a
| medical researcher!
| robbiep wrote:
| That's demonstrably not the reason why smokers get lung
| cancer and here is a thought experiment to prove it out.
|
| Alcohol is metabolised into formaldehyde. It's one of the
| reasons why we get hangovers and definitively the reason
| why people with the ALDH2*2 mutation get such bad
| hangovers (and flushes). Quantitatively, having more than
| a standard drink or two produces more formaldehyde than
| many cigarettes. A given unit persists for the same time
| in both smokers and drinkers, because it is further
| metabolised in the blood stream (which it reaches
| immediately in smokers).
|
| Perhaps it's some of the 200+ other chemicals (or a
| combination of them) that is the most likely aetiology of
| lung cancer?
| moremetadata wrote:
| You dont think cysteine intake like N-Acetyl Cysteine aka
| Salt and Vinegar crisps might influence the livers
| ability to metabolise said chemicals? NAC consumption
| will produce mucus very quickly in the lungs within
| minutes on an empty stomach and then maybe some glucose
| to increase CD4 cells to increase phagocytosis?
|
| Inhalation could be viewed as an internal topical
| application of formaldehyde... bypassing liver (and
| kidneys where applicable) metabolism. Maybe its the same
| reasons why some people inhale salt, for its
| antimicrobial activity, jigging with the bacteria's
| Na+K+-ATPase pump.
| moremetadata wrote:
| > jigging with the bacteria's Na+K+-ATPase pump
|
| I was kind of hoping you'd have come back to contest,
| because the inhalation of sodium is a topical application
| to recruit T Helper 17 cells to a site, even though that
| topical application happens to be the lungs.
|
| Ironically those people inhaling salt would probably be
| better off inhaling sodium bicarbonate because the
| bicarbonate will invariably through some localised
| chemical changes increase co2, and when co2 levels get to
| 1000-5000ppm in the lungs, the recruitment of immune
| cells increase.
| hollerith wrote:
| >N-Acetyl Cysteine aka Salt and Vinegar crisps
|
| Salt and vinegar crisps don't contain any NAC (although
| they do contain sodium acetate, which sounds similar).
| photochemsyn wrote:
| 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/
|
| 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-anti...
| asdff wrote:
| Functional antibiotic resistance is costly to maintain when
| there is no presence of antibiotics that would improve the
| fitness of these sub populations. One way to get around the
| issue of antibiotic resistance is to just cycle through
| different antibiotic compounds. A population will not maintain
| resistance to compounds not in its environment for very long.
|
| https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707769/
| elil17 wrote:
| Thank you for your excellent summary.
|
| How does antibiotic resistance in animals cross over to
| antibiotic resistance in humans?
| PeterisP wrote:
| Some bacteria infect both animals and humans, and there is
| also horizontal gene transfer between bacteria, so if someone
| is infected with two (or more!) different bacteria, (e.g. in
| a hospital environment - see
| https://pubmed.ncbi.nlm.nih.gov/30248271/), that can result
| in the relevant resistance genes to be transferred to another
| disease, creating a strain of it that is also resistant to
| that antibiotic.
| rowanG077 wrote:
| There are a ton of bacteria that infect both humans and
| animals. For example MRSA.
| ce4 wrote:
| Horizontal gene transfer:
| https://en.wikipedia.org/wiki/Horizontal_gene_transfer
| psychphysic wrote:
| 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.
| pauljurczak wrote:
| "a new versatile therapy for an imminent global health crisis"
|
| Do they have a crystal ball or know about a plan being
| implemented?
| adrianN wrote:
| 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 wrote:
| Its not that simple.
|
| Some rates of resistance are dropping.
| cinntaile wrote:
| They're talking about antibiotics resistance.
| jmyeet wrote:
| 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.
| Slava_Propanei wrote:
| [dead]
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