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Dual action antibiotic could make bacterial resistance nearly impossible
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- didgeoridoo 2y agoIt’s unclear why the same benefit couldn’t be achieved by mixing two traditional antibiotics with different mechanisms of action. Maybe the combined dosage would stress the liver too much?
- wkrsz 2y agoBacteria can develop resistance to individual antibiotic mechanism. Then two strains can swap resistance genes to produce a super-bug: https://asm.org/articles/2023/january/plasmids-and-the-spread-of-antibiotic-resistance-g https://asm.org/articles/2023/january/plasmids-and-the-sprea... My understanding is that in this case bacteria would have to develop resistance to two mechanisms at the same time, which is much more difficult. Mandatory quote: "Life, uh, finds a way"
- fluoridation 2y agoIsn't it exactly the same situation? In one case you have two substances that attack cells by two different mechanisms, and in the other you have a single substance that attacks cells by two different mechanisms. In either case a strain that doesn't have resistance to both mechanisms will get wiped out, since just one of them destroys the cells or prevents them from reproducing. Even if some sub-strains develop resistance to one of the mechanisms, it won't matter because they will get wiped out by the other.
- wkrsz 2y agoI meant that if you have two separate substances, we can reasonably assume they will also be used individually, giving bacteria chance to develop resistance. Then strains with different resistances meet in one organism and swap genes. Although that's extremely simplified. I recall reading that the usual mechanism is somewhat different. When you take one antibiotic to fight one pathogen, also attacks other bacteria in your gut microbiome (also those benign and even useful). Those bacterial also develop resistance. Unfortunately they can later share their resistance genes with harmful bacteria.
- fluoridation 2y agoOkay, but unless the older single action antibiotics are completely taken out of the market, it doesn't really matter, does it?
- proaralyst 2y agoI'm not a biologist, but I'm guessing that having the concentrations of two antibiotics peak at the same time etc is much much trickier than having one molecule with two mechanisms of effect. Thus in actual (not perfect) use you end up with both effects active within a bacterium at one time, rather than potentially having some distance between the peaks. From the article, it does look like they're smushing two antibiotic active sites into one molecule, so it seems a somewhat similar idea
- mordymoop 2y agoBut if doctors don’t always prescribe these two antibiotics to be used in tandem, then microbes will have an opportunity to evolve resistance to each one in isolation, putting those resistant genes out in the world. Whereas in this case, any bacteria ever encountering this drug will be hit by both mechanisms at once.
- abeppu 2y ago... but the article describes that the antibiotics being discussed combine structures from classes of antibiotics which are already used independently. > Macrolones are synthetic antibiotics that combine the structures of two widely used antibiotics with different mechanisms. Macrolides, such as erythromycin, block the ribosome, the protein manufacturing factories of the cell. Fluoroquinolones, such as ciprofloxacin, target a bacteria-specific enzyme called DNA gyrase. So if macrolides and fluoroquinolones are each used independently already, and strains resistant to each of them independently, and these strains have an opportunity to co-occur and do horizontal transfer, wouldn't we expect that to have resistance to a single drug that combines both mechanisms? I guess, when a strain develops resistance, is it to the mechanism overall (e.g. a more robust ribosome or differently shaped DNA gyrase enzyme) or is the resistance somehow specific to a specific molecule (e.g. some enzyme that finds and breaks-down the drug based on other aspects of its structure)?
- etiam 2y agoGood observations. There are many possible mechanisms for resistance, and with this involving bacteria I expect pretty much all are sooner or later used. Some ways are more specific to the substance, such as changing the target to fit worse or be less sensitive to the effect. Some can be quite general, such as actively pumping the molecules out of the cell. In these cases there won't probably won't be that much wiggle room for altering the targets. Ribosomes and DNA-associated enzymes tend to be very very busy doing critical work against a lot of substrates and products, and are already heavily optimized for their normal tasks. I'd say it's no coincidence these mechanisms were chosen for a novel antibiotic attempting to mitigate resistance development. Degrading the antibiotic, throwing it out, etc are still viable options, but it's still very nice to see someone finally trying to do this more right, even if basing it on elements of existing classes adds some risk that there are strong initialization states for resistance development out there.
- sottol 2y agoThe antibacterial resistance is often on small DNA loops called plasmids which are often and easily exchanged between bacterial species. I assume this has to do with that, either the resistance would have to develop twice in the main genome or twice on the same plasmid. In the normal dual antibacterial cases just developing a single resistance and acquiring the right plasmid is enough.
- s1artibartfast 2y agoGood question. Take many many antibacterial molecules to kill a bacteria, so there are two plausible methods. The first is that two compounds can have different pharmacokinetics. That is to say, they move through the body in different ways and have different concentration profiles. The second is about how they are used. Two separate compounds with the same pharmacokinetics could be effective if you use them in parallel, but you have to contend with the fact that real human users may not always use them that way. If two different companies make compound a and compound B, it is virtually impossible to prevent someone somewhere from using them separately
- chiefalchemist 2y agoAnd if, in this case, life does find a way, then what? Is this not a recipe to create a super super bug?
- badcppdev 2y agoIt's a probability game isn't it. There's a chance of that super super bug given normal antibiotics. But also chances are that any super super bug is going to have a downside that stops it spreading unhindered through other hosts or something like that. There's always the possibility of a microbe/prion/other that can attack and consume all DNA based life forms. Or a 'nearby' gamma ray burst that sterilises everything within 200 light years.
- badcppdev 2y agoI'm embarrassed to admit that I clicked into the comments looking for that, uh, quote.
- tristramb 2y ago"Evolution is smarter than you are" - Francis Crick
- Qwertious 2y agoEvolution isn't smart, it's just a hard worker that's extremely open-minded when it comes to results.
- etiam 2y agoThe reason two is harder is a bit subtle. Hitting the population with multiple mechanisms simultaneously masks the selective advantage of slightly better phenotypes against the individual attacks. There's a spread in individual characteristics, and if the attacks are applied independently, the more vulnerable individuals perish more readily and the genetic distribution goes on to trying states mainly near the more resilient ones against that attack. But faring a bit better against Attack-1 is practically no better than not, if Attack-2 is always going to wipe out all Attack-1-resistance phenotypes about equally anyway. Executed just right it attacks the conditions for gradual evolution by breaking most of the corrective signal.
- diath 2y agoLast year I was hospitalized and quarantined for Tuberculosis, which is fairly strong against antibiotics so the antibiotic therapy is 6 months long (minimum), and that's precisely how I was treated, by combining first 4 then 2 antibiotics in order to prevent the bacteria from developing resistance, but you're right, it's super bad for your liver, I've seen heavy alcoholic patients in the same ward that were refused treatment because "we would destroy your barely functioning liver and kill you", and watched them just die, but I don't think it completely prevents the bacteria from building resistance, it just minimizes the odds to a significant degree.
- amelius 2y agoWhat's the best way to allow the liver to recover after such heavy medication?
- rscho 2y agoDon't drink alcohol. Drink water. Eat healthy, not too much, mostly plants.
- bluGill 2y ago> mostly plants. This is in general good advice, but in the context of healing the liver plants are generally the type of poison your liver exists to filter in the first place, so a meat heavy diet is likely better. Of course you are trading longer term cardiovascular health for short term liver healing so don't do this for long, but if your liver is very damaged avoid plants as well for a short term.
- Retric 2y agoThat may seem logical, but actual testing shows a largely plant based diet is actually better for the liver. Enterohepatic Recirculation is heavily influenced by diet which is why fiber and specifically leafy greens seem to be helpful for liver heath. https://en.wikipedia.org/wiki/Enterohepatic_circulation https://en.wikipedia.org/wiki/Enterohepatic_circulation This is also one of the reasons activated charcoal is useful after ingesting a wide range of harmful substances.
- mpreda 2y agoTrimethoprim/sulfamethoxazole is a widely used such combination antibiotic. "Trimethoprim/sulfamethoxazole, sold under the brand name Bactrim among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections." https://en.wikipedia.org/wiki/Trimethoprim/sulfamethoxazole https://en.wikipedia.org/wiki/Trimethoprim/sulfamethoxazole
- aziaziazi 2y agoTo rephrase didgeoridoo : What are the advantage/drawbacks of the article method over Bactrim method ?
- whimsicalism 2y agoi think with combination antibiotics, you can’t guarantee that nobody in the world is using one of them on their own
- m3kw9 2y agosounds like they are underestimating nature here
- DennisP 2y agoMaybe. But you could have said the same about the smallpox vaccine, but look how that turned out.
- funnyenough 2y ago[flagged]
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- zabzonk 2y ago> 100 million times do you know how many bacteria, all mutating and swapping genes, there are out there? also, dual therapy, particularly for TB has been used for years, but TB is still with us.
- John23832 2y ago> also, dual therapy, particularly for TB has been used for years, but TB is still with us 1/4 people carry TB in the world. Most asymptomatic. TB been with humans as long as humans have been around, and it will be with humans as long as we're here. Multidrug Resistent TB is a thing though.
- gcanyon 2y agoBut drug resistance is already really hard to develop. As you say, there are an almost unfathomable number of -- let's say staph -- bacteria running around, infecting millions of people per year, and still it's taken most of a century to develop MRSA. 100 million times might make MRSA v2 take millennia to arrive.
- aziaziazi 2y agoAs we see an exponential grow or the human population, shouldn’t your estimation for v2 be pondered compared to v1 development?
- jajko 2y agoI dont think you understand the word exponential.
- aziaziazi 2y agoI think I do but I made the common mistake of mismatching exponential with accelerated growth. My interrogation hold : aren’t bacteria infections quantity (and therefore duplication and mutation) influenced by the growing number of host?
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- pfdietz 2y agoWell, aside from the generic defense mechanism of pumping unwanted chemicals out of the bacterial cell, or an enzyme for degrading the antibiotic. Multiple mutations could also occur if the cells are being exposed to sublethal amounts of the antibiotic, say in sewers (which would also be an environment for evolution of enzymes to degrade the chemical.)
- pulkitsh1234 2y agoDon't know much about microbiology, but saw this ( https://www.youtube.com/watch?v=VPSm9gJkPxU https://www.youtube.com/watch?v=VPSm9gJkPxU ) video about biological "motors" which allow for movement in the organisms (chemotaxis). In the end, they speculate that future antibiotics could target a bacteria's motors to disrupt its movement. Not sure how difficult will it be for the bacteria to gain resistance to this approach.
- dd_xplore 2y agoWhat's the issue? He has faith in something. But he's discussing the science without any religious stuff. Even then he never said anything along the lines that would compare the mechanism with creation of god or something. What's with all the hate?
- gcanyon 2y ago[flagged]
- hasperdi 2y agoThere's a bit of preaching at the end. What a turn off
- MobileVet 2y agoIt is fairly difficult to be perfectly objective about everything we discuss. We all bring our own bias and experiences to just about everything we do and say. In Dustin’s case, he is being open about his background and perspective. Isn’t that more commendable than trying to feign objectivity? Clearly you can agree or disagree but being annoyed at his transparency seems to neglect consideration for the alternative.
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- 1992spacemovie 2y ago[flagged]
- shrimp_emoji 2y ago[flagged]
- dang 2y agoPlease don't do this here.
- jncfhnb 2y agoI’ve heard for years that antibiotic resistant bacteria don’t really seem to be a threat because they tend not be very successful in the wild. Like it’s going to be, at best, a very localized outbreak because competitive pressures don’t reward the trade offs. That’s still true?
- sva_ 2y agoThey are a problem for people who are immunocompromised. In particular they spread in hospital settings.
- whatever1 2y agoMy close relative almost died from one. He caught it in the hospital after a routine surgery. His condition deteriorated dramatically, was in a comma for a couple of days but thankfully survived. After he recovered they could still detect the bacteria dormant in the liver for three years, at which point he re entered the hospital to start a heavier multi-antibiotic treatment plan that could potentially evict the bacteria but could also cost his liver. He won after all, but his health condition overall never returned to the original.
- etiam 2y agoMaking extra genetic material and their resistance products can be a liability if they're useless (and so would slowly be lost), but there's all sorts of chemical combat between microbes in lots of environments and you can't be sure the resistance adaptations aren't good for other things too, potentially something different.
- bluGill 2y agoHospitals are an environment where they have the advantage and where humans who are most vulnerable are. Outside of a hospital they don't do as well, but the local environments they do well in are still important even if they are a minority. Also, if the bacteria targets humans or things humans treat (cats...) anything not resistant will not survive as well because when we detect sickness we treat it and select for anything resistant.
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- ninetyninenine 2y agoIn the future they may find two antagonistic vulnerabilities. Evolving resistance to one vulnerability makes you more vulnerable to the other.
- elzbardico 2y agoNever understimate what armies of over-prescribing GPs can do.
- sickofparadox 2y agoOr what an army of pigs being fed the pill "just in case" can cook up.
- kylehotchkiss 2y agoStep 1: We are overconfident that bacteria won't become resistant to this formula Step 2: Formula sold to developing countries pharmaceutical industry Step 3: Antibiotic given to every man, woman, and child with even the most trivial of symptoms Step 4: Widespread bacterial resistance to dual action antibiotic. Step 5: rinse, repeat We need better antibiotic distribution practices before we unleash more formulas on the world. Anything this strong should never be given to farm animals and should not be given to any developing country not willing to implement strong access control on a patient by patient basis (ie verified infection with bacteria that can be controlled with the formula and verified completion of course)
- inglor_cz 2y agoStep 3: even worse, to every pig and cow, to make them grow faster in worse conditions. I think the main problem is in lack of awareness. People don't understand that antibiotics have downsides. But how to spread awareness without swinging the pendulum too far and creating an ugly stepsister of the anti-vax movement? It certainly seems that humanity doesn't have much capacity for nuanced thought when it comes to "chemicals".
- kylehotchkiss 2y agohttps://www.aljazeera.com/features/2016/8/15/what-is-killing-indias-babies https://www.aljazeera.com/features/2016/8/15/what-is-killing... My argument stems from stories from India of newborns getting multidrug resistant bacteria shortly after birth, presumably from the hospital they were born in because standard medical practice in India is to be given antibiotics for even a minor cough (I have been there long enough and witnessed this firsthand). It’d be really cool if pharmacies there would put up more barriers to distributing these!
- hughdbrown 2y agoHumans: Dual action antibiotic could make bacterial resistance nearly impossible. Bacteria: Hold my beer.