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."
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.
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.
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.
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.
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".
> 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.
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.
> 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.
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.
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).
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.
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.
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.
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.
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.
> 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.
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.
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.
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?
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.
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.
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.
> 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.
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
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
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."
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)
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."
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.
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.
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.
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).
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.
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?
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.
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.
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.
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!
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?
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.
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.
I’m sorry, but I’m having a lot of trouble following your tangential and, from my position, erratic, line of thought.
You started off with the minute quantity of formaldehyde being the reason the combustion product of tobacco, which contains dozens to hundreds of known carcinogens, causes lung cancer. It is barely even associated with fucking cancer in alcoholics, who exist with significantly higher levels. And since it’s distributed in body water instantaneously, you can’t claim local effect.
Then you’ve gone onto NAC and sodium and creatinine.
What is the point you’re trying to put across? Because it’s scatterbrained, point and shoot, seems to have little in the way of actual scientific literacy beyond that picked up through the deep search of narrow knowledge and the subsequent cross linking, I believe somewhat erroneously at times, from the spars you have thrown between where we started to NAC, sodium and somehow co2 reaching 5000ppm.
Let’s just focus on that last part for a second. Clearly you have not studied respiratory physiology in any way, shape or form. In a functioning human who is not in respiratory arrest, it is NOT POSSIBLE to have alveolar (or frankly anywhere else in the lungs) concentrations of CO2 of 500-1000.
It would mean a significant respiratory acidosis and death, because the efficiency of gas exchange is such that the alveolar concentration MUST reflect the venous gas level.
On reflection, you really haven’t given anything to provide anything to discuss against besides a wildly moving target of quasi linked subjects that seem to be the subject of your fascination, an impression that this is a hobby interest rather than a lifelong learning.
If I have misjudged, I hope you will provide a more coherent explanation of why I have and how the disparate subject areas you have discussed are linked
Its either NAC or ALCAR which smells like Salt and Vinegar crisps, but NAC will certainly help the liver deal with state licenced poisons like alcohol and paracetamol aka acetaminophen.
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)
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.
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)
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.
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.
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.
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.
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.
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
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.
> 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
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;
> 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.
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.
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.
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."