"...strikes multiple targets, including cell walls...Since the lipid structures it attacks don’t evolve as quickly as frequently mutating proteins, it may take the bacteria longer than usual to develop a survival tactic."
Proteins change often and quickly, but basic cell structures may take longer or never adapt.
But I'm not a pathobiologist, I just play one on the Internet
So do the β-Lactam antibiotics (e.g. penicillin), but that doesn't stop a host of unrelated resistance mechanisms: enzymes that directly attack it, mutations to the protein(s) that are necessary for entry into the bacteria, and probably the pumps that actively remove various antibiotics.
Given that this was discovered from existing bacteria, there's a significant chance nature has already done the first and last of those. The middle mechanism is likely possible for any bacteria, if you have enough to start with (there's nothing I could find with Google in a minute to describe teixobactin's transport mechanism).
In general there was a rule of thumb when I was doing microbiology of this exact nature (an antibiotic created by some strains of E. Coli), if you exposed a million bacteria cells to a generic antibiotic, 1 would would survive due to a mutation (a useful number in microbiology, likely dead meat in the body). Streptomycin was more effective, 1 in a billion.
ADDED: it's implied by the Nature abstract that the researchers have tried this general approach, that they were not able to find spontaneous resistance mutations in a couple of the standard nasties. But extending on the above thesis, ecologically, there's a respectable chance some bacteria out there have developed defenses. It's a jungle out there, and e.g. in your gut, that's why fungi and bacteria developed antibiotics in the first place. They aren't expending resources just to allow us to kill the inconvenient ones.
From the Nature article, the claim that resistance to teixobactin is hard is based on an attempt by the authors to induce resistance by culturing S. aureus or M. tuberculosis in the presence of sub-lethal concentrations of teixobactin for 27 days and seeing if resistant clones evolved. They did not observe any. That doesn't mean it's impossible, though. Plasmids for example are a source of resistance that doesn't require mutations.
Edit: deleted incorrect information about b-lactamase.
Nature asked me for $$$ to read the article, so ... from your description, that's leaving out the hard, fast test of just culturing several billion of those, adding a lethal concentration and seeing if there are any survivors. Which is how I gather one found spontaneous transport mutations, at least circa 1977. The state of the art has likely improved, and these guys used novel microbiological methods to find the bacteria that produce teixobactin in the first place.
ADDED: thanks to betatim's link to the full text, I've skimmed it and read the discussion, and teixobactin sound quite promising. They haven't found any protein to which it binds, and they think it binds to an "Achilles's heel" in the outer cell wall. The method described to generate resistance was their most extreme attempt, so I assume they tried the fast way, and I can see why it didn't work.
Ecologically, they believe there's little gene (e.g. plasmid) transfer between these soil bacteria and human pathogens, and the "30 year" bit came from experience with vancomycin, to which it has a lot of similarity. And they've done lots of tests for human toxicity and effectiveness in mammals. It's still early in the process, but a degree of fuss is warranted, especially due to their discovery method.
Here are the pertinent bits regarding resistance, in summary it implies that spontaneous resistance will be difficult, But... "life has a way":
>We were unable to obtain mutants of S. aureus or
M. tuberculosis resistant to teixobactin even when plating on media with a low dose (4 X MIC [minimal inhibitory concentration]) of the compound. Serial passage of S.aureus in the presence of sub-MIC levels of teixobactin over a period of 27 days failed to produce resistant mutants as well (Fig. 2d, Supplementary Discussion)
From the Supplementary information:
>Cells were added to teixobactin present at 0.25xMIC, 0.5xMIC,1xMIC,2xMIC and 224xMIC. At 24 hour intervals, the cultures were checked for growth. Cultures from the second highest concentrations that allowed growth (OD600≥2) were diluted 1:100 into fresh media containing 0.25xMIC, 0.5xMIC,1xMIC,2xMIC and 4xMIC of teixobactin. This serial passaging was repeated daily for 30 days. Any cultures that grew at higher than the MIC levels were passaged on drug free MHA plates and the MIC was then determined by broth microdilution. No resistant mutants were obtained. This experiment was repeated, and produced the same negative result. In order to maximize the chance of obtaining a resistant mutant, we performed an additional experiment with very small incremental increases in the drug concentration. Cells were added to a series of tubes with small differences in the concentration of teixobactin (0.06xMIC, 0.25xMIC, 0.5xMIC, 0.75xMIC,1xMIC, 1.25xMIC, 1.5xMIC, and 2xMIC). At 24 hour intervals, cultures from the highest concentration that allowed growth to a minimum OD600 of 0.2 were diluted 1:100 into fresh medium containing 0.06xMIC, 0.25xMIC, 0.5xMIC, 0.75xMIC,351xMIC, 1.25xMIC, 1.5xMIC, and 2xMIC. This passaging was repeated for 27 days. Cultures that grew at levels higher than the MIC were passaged on drug free MHA plates, and the MIC was determined. For teixobactin, there were no mutants with an MIC greater than the parent S. aureus ATCC 29213.
What they're describing here is an intensive selection process for resistance. It's debatably much more intensive than nature would ever perform: they're growing bacteria in the presence of various dilutions of the antibiotic, taking a sample of the culture, diluting it 100-fold, and repeating the selection many (~30) times. Then they look for any bugs that develop resistance. None were found. Even if you had a truly pathological patient (i.e. someone who was doing his level best to mis-use an antibiotic), it wouldn't come close to this level of selective pressure for antibiotic resistance.
Moreover, there's a strong biochemical argument against resistance: the region that the antibiotic targets is highly conserved, which means that it's probably functionally necessary. The bug is therefore unlikely to evolve away from the threat. This is important, because it's that most likely avenue for antibiotic resistance, energetically speaking: it doesn't cost anything for an organism to mutate a weakly conserved gene, so they do it once, and pass it on to every subsequent generation with no penalty.
The antibiotic is just a peptide, so in theory you could see some sort of specialized peptidase evolve from an existing gene...but the problem is that the bug would have to then carry around that gene and express it constantly (or even less likely: evolve a sensing system that allows for selective expression). It's a highly unlikely thing, and virtually impossible to maintain over multiple generations without constant selective pressure. Bacteria do not like to hold on to genes that they don't need.
Nothing is impossible over evolutionary time, of course, but the researchers don't seem to be overstating their case here.
Without having read the article too closely, teixobactin appears to be binding the lipids of the bacterial cell wall. It might be hard to evolve simple resistance to this (and the authors support this by experiment) as this would require that the bacterium changes the composition of its membranes, rather than evolve a mutated enzyme, which is how most spontaneous resistance occurs.
However, that does not exclude the possibility of the bacterium acquiring a plasmid or phage carrying an enzyme that inactives teixobactin. This particular mode of acquiring antibiotic resistance is quite common.
Nevertheless, this finding does seem to be quite a big deal. A novel broad-spectum antibiotic where spontaneous resistance is unlikely is a pretty powerful addition to the pharmacopeia.
"acquiring a plasmid or phage carrying an enzyme that inactives teixobactin. This particular mode of acquiring antibiotic resistance is quite common."
Right, which is why I said the bit about bacteria kicking out genes that they don't need. Bacteria will "eject" a plasmid within a generation or two if they no longer need the gene(s) in question. Replicating a big gob of easily-ejectable DNA is not something bacteria do unless there's a good reason to do it.
Basically, for plasmid resistance to propagate, you need to have constant exposure to the antibiotic in question, or the resistance gene needs to be stably integrated into the bacterial genome. The former doesn't happen until an antibiotic is in extremely wide use, and the latter is one more rare step on top of an already unlikely chain of events.
It's a highly unlikely thing, and virtually impossible to maintain over multiple generations without constant selective pressure. Bacteria are quickly out-competed by genetic variants with fewer expressing genes that they don't need.
BTW: do you have any links/data re the relative 'cost' of expressing unneeded genes?
Relative to what? I don't know if there have been papers on the thermodynamics of it, but it's a complex process that depends on a bunch of factors: the size of the organism, the size of the genome, the size of the new protein, the level of expression, etc.
Empirically, everyone who has done lab work with bacteria knows that they'll quickly (i.e. within a few generations) kick out plasmids unless there's selective pressure to keep them. Genes are more likely to stick around than plasmids (since they're directly integrated in the organism's genome, and there's less of an energetic cost to accumulating DNA sequence), but stable genome transformation is slow/unlikely, and bacteria will still find a way to disable un-needed genes in a relatively short period of evolutionary time.
"Bacteria are quickly out-competed by genetic variants with fewer expressing genes that they don't need." This has not been true for MRSA, where transmission of resistant organisms in the community was sustained despite there not being particularly intense selective pressure in the community. Last I checked (I don't work in community transmission as much) we don't have a firm handle on why that's true, but I'd caution against simply assuming that resistant organisms will be out competed absent selective pressure.
Beyond that, even if they are out competed, that's not sufficient. They need to be out competed to extinction.
MRSA is due to the mecA gene, which is integrated into the S. Aureus genome. It's not plasmid-mediated resistance, which means that it's less likely to disappear from bacterial populations, even in the absence of selective pressure:
There's also regulatory genes that may be present, there are 6 known varieties of the whole gene cassette, with 5 further subtypes based on these regulators, so in the absence of β-Lactam antibiotics it sounds like a lot of them will be fit.
True - but the post I was responding to wasn't talking about plasmid-mediated resistance, but rather a broad assertion that a competitive disadvantage will take care of things. That's a strong assumption for which we have a counter example.
No. Beta-lactams inhibit cell wall synthesis by binding with penicillin binding proteins and preventing their function. Beta-lactamase is a resistance mechanism against this family of drugs.
Microbiologist here. Your last sentence is perhaps not correct, or else I am not understanding it well enough.
Plasmids are indeed a source of resistance, but plasmids just contain genetic code. They are considered mobile since they are easily transferable between bacteria (including different species). So for a plasmid to encode resistance to this new antibiotic, it would need to contain the code for a protein which disrupts the action for the antibiotic. For example, the plasmid would encode for an enzyme that digests the antibiotic at a faster rate than it can work, or bind to the target of the antibiotic with a higher affinity.
So maybe what you were getting at is that a plasmid exists out in the world that encodes the protein for resistance, it just didn't happen to exist in the researchers niche world, or doesn't rely on a random mutation to become a resistance product.
So maybe what you were getting at is that a plasmid exists out in the world that encodes the protein for resistance, it just didn't happen to exist in the researchers niche world....
Per cowsandmilk the senior author of the publication "is one of the world's foremost experts on antibiotic resistance". The paper discusses how there seems to be little gene transfer between the "biome" of soil bacteria from which this and vancomycin come and the relevant pathogens. They specifically cite that it took 30 years for any resistance to develop to vancomycin.
Whereas I'd add β-Lactam antibiotics seem to be pretty common (they are derived from at least 5 different organisms that I just counted in Wikipedia), and β-Lactamases are all too common; per Wikipedia https://en.wikipedia.org/wiki/Beta-lactamase the first was discovered in 1940 before penicillin was in clinical use.
It's too bad there's no easy way to make resistance work for us, instead of against us. Like finding something else for these to infect, having them get resistance to the nasty bug, then using the same method to get rid of it.
Many of the antibiotics are made naturally by fungus to combat bacteria. Once discovered, we just create a synthetic method to prepare them, and perhaps improve the effectiveness and reduce the collateral effects. The canonical example is penicillin http://en.wikipedia.org/wiki/Penicillin#History
Errr, spontaneous mutation?? Selection pressure for such mutations that are still survivable for the bacteria?
I just described a very rough screening method, pcrh quotes from the Nature article other extreme efforts tried. These don't produce specific types of mutations, they just discover if there are any "easy" ones. E.g. the E. Coli antibiotic I mentioned had to be transported across the membrane bacterium by a protein.
The lab I did part of a summer's research was working with the enterobactin iron scavenging mechanism in E. Coli (https://en.wikipedia.org/wiki/Enterobactin). If grown in seriously iron free condition (e.g. glassware was soaked in HCl, and then bathed in deionized water for days), it would synthesize iron binding enterobactin and send it out into the environment, and there was a protein on the membrane surface that would accept the enterobactin+iron complex.
This also turned out to be the protein that accepted this antibiotic into E. Coli. It appeared that some of the mutations that allowed this were either point or deletion mutations of that protein, either it was deranged or cut off in some location, or outright deleted (missing from the bacteria's set of genes in its DNA).
So this survival mechanism is one of just not letting the antibiotic inside in the first place, which is how it appears teixobactin producing bacteria survive it. They appear to synthesize and expel it, and they don't have cell walls allowing it to get back in.
I am a microbiologist. It is not that you want to target basic cell structures, but you want to either target multiple systems, or target systems that have a large number of modular interactions. It is relatively easy to create/discover new chemicals that kill bacteria specifically, but if these new chemicals only target one specific component then the bacteria rapidly evolve resistance. All the good antibiotics we have interact with complex systems like ribosomes that are made up of multiple interacting modules.
The reason we are having trouble finding new classes of antibiotics is that we are already have chemicals that target most of the interacting and essential cellular modules in bacteria. If you already are targeting 90% of all the possible targets you will find it very hard to discover any new classes of antibiotics.
Of course the solution is not to worry too much about finding new classes and just keep tweaking the current antibiotics to keep ahead of the bacteria. The only problem with this strategy is that the economics of antibiotic development is totally broken so the pharmaceutical companies have in the main stopped spending money on finding new antibiotics. What we need to work on is a new way of paying for new antibiotic development.
It seems strange to me that we're willing to spend trillions of tax dollars on the military, but when it comes to the bacteria that attack us every day, we throw up our hands and just take whatever the free market finds profitable to provide.
Plus drugs are one of the very most heavily regulated "free markets" in the US ... and as others have noted, there are laws like the Bayh-Dole Act (https://en.wikipedia.org/wiki/Bayh%E2%80%93Dole_Act) which can make the process much more of a government-non-profit-corporate partnership. There is also a "Generating Antibiotic Incentives Now" (GAIN) in effect, with an bipartisan Antibiotic Development to Advance Patient Treatment in the works.
So, no, we don't "just take whatever the free market finds profitable to provide", where "profitable" has "the visible foot" of the government strongly weighting one side of the balance scale. Not to mention very strong medical policy to restrict new novel antibiotics like this one to the cases where they're really needed.
The medical policy is a major component of the problem. What the drug companies have discovered is if they release a new antibiotic that the doctors put it on the shelf with the plan to only use the antibiotic in emergencies. Of course when this happens the drug company makes no money and so rightly concludes that antibiotic development is not profitable.
There have been lots of proposals to overcome this. My personal favourite is each country agrees to pay a straight cash bonus for each new antibiotic developed with a different valued bonus in proportion to the need. The drug companies would then not need to worry if the antibiotic was used or not and we would have on tap new antibiotics to use as resistance arises.
They author's state "it should be used, if it gets successfully developed, as broadly as possible" - because they believe it is robust against bacteria developing resistance.
Knowing nothing about this area... isn't this a bad idea because board use would increase the risk of resistance appearing and would mean those bacteria resistant to this would be extremely resistant to most other treatments aw well (given this drug has multiple modes of attack)?
Apparently they have a very plausible reason to think it will be robust: It attacks cell walls, which are structural, rather than receptors (I think I'm using the term correctly) that are proteins and prone to mutations.
It's basically the same reason we don't fear bacteria to develop resistance to boiling or alcohol disinfectant.
There are some archeas (and a few bacterias) that support boiling temperature, but IIRC they don't like meatware because it's too cold for them. http://en.wikipedia.org/wiki/Hyperthermophile
I did a project on mycobacteria in college, and its not surprising that some of these are resistant to alcohol. These are bacteria that produce a hard protein shell that protect colonies of bacteria, and they can be difficult to attack or scrub off.
Mycobacterium Abscessus, in particular is great at surviving in low-carbon environments (with very little food), and its protective shell and clustering formation protects it from low levels of chlorine. I cultured shower heads, sink faucets, and soda fountains in order to find them. Nasty stuff.
I wonder if you could get a system set up where, once we start using this, we put all the old antibiotics on a shelf. If bacteria never are exposed to them, they'll eventually lose their resistance, and so when we pull them out again they'll be almost as good as new.
EDIT further down people are making the same point (I think)
Actually, bacteria are, shall we say, particularly mutable (only one strand of genomic DNA, plus plasimids if they're useful), and they can do so rapidly.
It's an issue of selection pressures. If they live in a competitive environment, which includes competing against each other, then the most "fit" ones win by out reproducing the competition. Mutations that made them more fit in an environment rife with antibiotic X may be mostly harmless in the absence of X, or might consume resources that can ill be afforded. See e.g. this subthread for more discussion: https://news.ycombinator.com/item?id=8853232
There is a price to be paid for those defensive abilities. If paying that price no longer affords any benefit that would put selective pressure on removing those now needless defenses.
If it has the same relative safety of use as penicillin lines of antibiotics, but is more robust in its method of action to prevent resistance occurring as easily, then my guess would be it would be preferable to use as widely as possible.
The idea is that drug resistance comes with a metabolic cost. We're making them do something to survive that we didn't before, and it's going to come at a cost.
If we think of them like cars--armoured ones are extremely rare. However, if we started randomly shooting at cars, and did so for a protracted period, we would eventually see them become more common. The fact they're slower, don't turn as well, and use more fuel is now negligible because of the excessive benefit of it's contents not being shredded.
If the implementation of this new antibiotic came with a moratorium on the prescription of penicillin, then we would be targeting the population as a whole with an RPG. It doesn't matter if you're armoured against bullets anymore. Both the normal and the resistant will be put under the identical survival pressures, which should mean it is more effective against the resistant strains as these won't be as fast to replicate.
The problem from what I understand is that tackling antibiotic resistant drugs with drugs designed for antibiotic bacteria, just makes super bugs.
Essentially if we cleared the roads of regular cars and left ourselves with armoured cars, and then start firing RPGs at them, we'll end up with vehicles resistant to those. We will end up with APC's on the road.
If we implemented a moratorium on penicillin strain antibiotics, we could potentially reverse the current epidemic of multi-drug resistant strains. It would be like starting anew - assuming there's no genes that are equally beneficial against both drugs.
That's my understanding of the reasoning behind suggesting broad use, but I could be way off.
That seems to be a reasonable thought, although incredibly difficult to prove.
Primates and guinea pigs both dropped the ability to synthesize Vitamin C, through different mutations. Now both species have to consume it in their diet to survive.
Incidentally, the story of the broken Vitamin C gene in primates and guinea pigs is the main argument that gets used to show how the theory of evolution is supported. In all primates, including humans, the gene to make Vitamin C is in our DNA, but mutated so that it is not usable. But all primates have the mutated gene in the same place. Guinea pigs have a different mutation to the gene. The chance that all primates had the mutation in the same location simultaneously is very remote, suggesting all primates shared an ancestor that developed the mutation.
Which is all quite interesting when you think about it. I wonder what else that mutated gene is doing in primates for the mutation to be so successfully conserved.
I wouldn't do something stupid like give it to every single head of livestock in the world (cough) but the great thing about antibiotic-resistant bacteria is that they're not resistant to all antibiotics at once. Without the evolutionary pressure to stay resistant to antibiotic B, a bacteria can be resistant to antibiotic A but not so much A and B at the same time. (Which is why things like MRSA are treated with very old and unpopular antibiotics).
Any new antibiotic makes this approach even better, because if you have A, B, C, D, and now E, now the bacteria has to be resistant to all five at once, which is a lot of useless genes to hold onto.
Yes. If it takes 30 years for this drug to become resistant, but 5 or 10 for other antibiotics... then a sound strategy is to use the long-lasting drug, and save the drugs with a shorter lifespan as second, or third tier. This will slow the development of resistance, so they will last longer, and we'll have a broader range of working antibiotics at any given time. Which means more infections successfully treated, and more lives saved. Win!
If we eliminated treatment with drugs with resistances against them, we'd no longer be artificially selecting for those bacteria, which would mean the bacteria that naturally performed better would be the most likely to survive.
Essentially if we stop treating with the drugs with resistances against them, we'd eventually end up with a bacteria gene pool that resembled the original pre-resistant one, where resistant bacteria were replication errors that were drowned out by natural selection.
The only issue is we can't do that without sacrificing millions of lives. So having a drug that works via completely different mechanisms would fulfil both.
This is exactly what we've been doing for decades. When you get an antibiotic-resistant infection, like I have twice, they just give you older antibiotics. So the more antibiotics you have, the better, because it's harder for a bacteria to be resistant to more and more antibiotics at once.
Surely only using it in cases where other antibiotics hadn't proven successful would be a better approach so that you don't give bacteria much opportunity to become resistant.
Broad use of antibiotics in cases where it wasn't needed is exactly how we got into this problem in the first place.
Perhaps learning from history would be the most prudent approach.
Antibiotic resistance has a fitness penalty. If we switch to this new antibiotic for long enough, bacteria may lose their resistance to our current antibiotics.
I'm assuming their suggestion is to use this drug for the next 30 years, and by the time bacteria become resistant to it we can start using our old antibiotics again.
Antibiotic resistance does not necessarily have a strong fitness penalty - the spread of community-resistant MRSA is largely in environments where there isn't strong selective pressure against susceptible strains.
I think some in depth academic research would be required to determine the optimal strategy. Intuitive strategies may not be as good as some counter-intuitive options.
I'm not qualified to answer either way, I imagine several people could get PhDs finding out. It's too important to handle quickly
If this actually did get to market, it wouldn't be used broadly. Doctors and hospital already follow antibiotic stewardship policies that would limit drugs like this last-line uses.
Sure, they hand out the antibiotics where resistance has already developed, but trust me, the "last ditch effort" antibiotics (like vancomycin) don't get used broadly at all.
Vancomycin is used routinely (at least in the three hospitals I work in) and it is far from a last ditch drug. That has shifted to Linezolid and Daptomcyin. In the three hospitals I work at, medicine doctors must consult Infectious Disease doctors for approval to place patients on those therapies.
The parent post was referring to GPs, which at least in the U.S. aren't often operating in hospitals, and certainly don't get ID consults.
Vancomycin is the drug of choice for several major infections that are of a concern to hospitals (MRSA, C. difficile) because there's already pretty established resistance mechanisms. There are definitely some "more last ditch" drugs, but Vancomycin is kind of the first of the "Now we bring out the big guns" antibiotics.
Partially because it's a PITA to give to patients, and has some toxicity problems.
"Last ditch" is a poor choice of words. The point I was trying to make is that if you come to you doc with the sniffles, it's unlikely you're going to get an Rx for vancomycin.
Depends on the antibiotic. GPs don't hand out vancomycin like candy, for example. Of course, that's also because vancomycin is a pretty brutal drug all things considered.
That's kind of the perverse incentive here, right?
To recoup your costs, you need to sell as much as possible--but in doing so, you render your own product obsolete due to continuing counter-evolution by the target species.
Which is why one of the suggestions for improving antibiotic development is to heavily subsidize it - working antibiotics are a public good, and if you remove the need to sell drugs in order to pay for their development, you remove the incentive to use them too widely.
"The research was paid for by the National Institutes of Health and the German government (some co-authors work at the University of Bonn). Northeastern University holds a patent on the method of producing drugs and licensed the patent to a private company, NovoBiotic Pharmaceuticals, in Cambridge, Mass., which owns the rights to any compounds produced. Dr. Lewis is a paid consultant to the company."
If the research was paid for by the National Institutes of Health, why is the patent privately owned? This does not seem fair to taxpayers.
This is not only allowed, it's encouraged by legislation called the Bayh-Dole Act. The general thought is that there would be no incentive for anyone to do clinical trials on the drug, which can get quite expensive, if they don't have some protection for exclusive use. Many, if not most drugs proceed starting from academic research funded by governmental support.
I'll also add that the educational institute who received the government funds out-licenses the drug while maintaining a royalty interest in it. Lyrica came out of Northwestern and they build a brand new, shiny chemistry building out of the royalties.
Why is that bad? Shouldn't the discoverers of pregabalin, who helped millions in excruciating incurable chronic pain, receive a portion of the profit from the sales of the drug to build facilities for future research?
That seems like a well-formed feedback loop to me.
I'm not saying it's bad at all! I'm just pointing out that the academics who invent something and pass it to a biotech company for development get something in return!
Cynically, even if the school gets 100% of the profits, the feedback loop of "encourage drug development, get paid" functions properly. They would only have to pay their researchers just enough to continue working...
$100M-500M gets thrown around [1] but it's hard to find good data. This might seem not too high, but many drugs fail, and often fail at the most costly step (phase III). So you have to be sure to factor that failure rate in.
Depends on what indication they are trying to get. A handy estimate is that a phase III trial costs $15K/person/year. If they aim for a 1000 person trial of 6 month duration, you're looking at $15M just for the phase 3 (I doubled it since they typically run two). However, that's a small trial.
Fidaxomycin, which was developed by Optimer Pharmaceuticals to treat C. difficle, was relatively inexpensive to run. I want to say in the vicinity of $100 million
My naive instinct is that there should be some sort of split, not just having the university hold the full patent and income resulting from it, but I do think there should be some sweat equity for the researchers. Similar to how if you're raising money for a company, you don't have to sell your entire stake.
(This gets weird with the distinction between the researchers and the university as well, but that's a separate issue.)
Often university patent agreements are flexible, but agreements like 1/3 to research team, 1/3 to university (with some set aside for the hosting department), and 1/3 to the funding agency (depending on what's allowed by law) are not atypical.
A successful company will pay back the government many multiples of its investment in the form of corporate and income taxes. Also, financial incentives incentivize entrepreneurs to make the venture successful. Imagine the government taking over the commercialization of the drug...
No, harsh experience with Communist, socialist and Fascist regimes shows this is a universal human problem, with far worse e.g. environmental results. If you have independent companies do stuff, the government(s) they operate under, and people using the mechanisms of those governments, tend to check them. The alternatives remove those checks altogether.
Consolidating power tends to cause these sort of issues. It doesn't matter what the label of the system is, Communist, Socialist, Fascist, Capitalist.
While capitalism "won" these battles in the past and is better than authoritarianism, at the present moment, capitalism is destroying us all. Our version of capitalism is the new authoritarian regime evolving toward fascism. Like any authoritarian regime, our capitalism has effective marketing & it's believers.
"She died a famous woman denying her wounds; denying her wounds came from the same source as her power"
-- Power, by Adrienne Rich (About Marie Curie)
So the answer is not as simple as sprinkling some "capitalism" on it. We need more love of self & others, more transparency, more equality, environmental protection, systemic design, awareness of the impact of our actions, awareness of politics, decentralization, less emphasis on money and more emphasis on community, etc.
"If you name me, you negate me. By giving me a name, a label, you negate all of the other things I could possibly be." -- Søren Kierkegaard.
The answer is not a label. The answer is our actions. That is who we are.
"We need more love of self & others, more transparency, more equality, environmental protection, systemic design, awareness of the impact of our actions, awareness of politics, decentralization, less emphasis on money and more emphasis on community, etc."
How do you propose to bring about a more utopian society with the above characteristics?
How plastic do you think human nature is?
(Note that I came of political age during the tail end of the cultural '60s. I have heard all of the above before....)
> How do you propose to bring about a more utopian society with the above characteristics?
Individual people have to care about these values & resist the imposed values of ego, greed, competition, materialism, ridicule, nationalism, violence, being "right", "getting mine", etc. It takes people leading & living the life of these values. If others resonate with these new values, then a movement is built.
All I can do is love myself & others. I see my own life as an archetype of our greater successes & failures; doing my work has a positive impact on those around me.
> (Note that I came of political age during the tail end of the cultural '60s. I have heard all of the above before....)
Like anything else of nuance, it takes creative iteration.
The '60s changed our understanding of freedom, love, & compassion. The upheaval healed, perpetuated, & created trauma on our souls.
The '60s had a lot of energy breaking social bounds. Sex, drugs, & rock-n-roll, while liberating, is not necessarily the most sustainable emphasis.
Many people went down a more esoteric path learning about ego & love. We can utilize our advances in communication, social understanding, global reach, experience, etc to shift our values to be harmonious with each other & our environment. It's necessary to our survival, so I have faith that we will evolve, just like we have many times in the past (i.e. tools, fire, civilization, etc).
There are years of work and millions of dollars between discovering or inventing a chemical that seems to have a certain health benefit and having a safe, thoroughly tested drug ready for manufacturing. It's the difference between science and engineering.
While there are new strains this would be a new class WHICH means AWESOME if it works out. Since this is so early I am not hoping for much.
My son had cancer and he had a staph infection that was septic (AKA in his blood through out his body). Non-resistant = 95% cure rate resistant strain and if you have a compromised immune system less then 50% cure rate. Good news for cancer patients and glad to see it coming down the track.
This is a bit of an odd article. The FDA has approved a number of different antibiotics over the past year. Most are not new mechanisms of action, but they are new products that have different profiles against different resistant bacteria.
The other issue is that this is very early in development. I really hope it gets through trials, but there are graveyards full of promising antibiotics that failed.
I think the reliance on new classes is a bit excessive. There are numerous new beta-lactams that have come out that are still in the same class, but have overcome (some of) the resistance issues.
A new class would be great, but even different drugs from the same class would be great as well.
Their experimental approach was interesting and hopefully will lead to more discoveries. I feel like this drug is already being overhyped however. It doesn't work for gram negative bacteria, which are responsible for most of the serious and scary multi drug resistant infections.
Also, assuming it doesn't have weird toxicity in people, or unfavourable pharmacokinetics, the author's suggestion that we should give it to everyone is a bit cute, given that it will almost certainly cost north of $200 per day if it gets to market...
Peptide antibiotics can have some issues. A recent new peptide antibiotic called Daptomycin [1] can't be used for pneumonia for example, because it is inhibited by pulmonary surfactant.
Is $200/day a lot for a highly effective antibiotic?
Genuine question--my experience is that a serious hospital stay racks up charges starting in the high five figures (and the sky's the limit), and if there's an antibiotic that's merely a couple thousand a day, it'd certainly be very cost effective.
> my experience is that a serious hospital stay racks up charges starting in the high five figures (and the sky's the limit)
This is USA specific. Day in hospital in Poland costs around 100-400 USD (and that's for people without insurance, so for >95% of population it's free). It's probably worse quality, but still..
I don't understand how you get so outrageus prices for healthcare in USA.
When they made roundup they expected plants would never be able to be resistant to it[1].
And in fact plants did not become resistant in the way they expected. Trouble is plants found a completely different way to resist roundup that no one expected.
Their claim that bacteria would not become resistant to this antibiotic is rubbish. They do have the ability to determine that.
If they actually want to know then deliberately try to (carefully) create resistant bacteria by continuously giving them low levels of antibiotic and slowly increasing it.
> If they actually want to know then deliberately try to (carefully) create resistant bacteria by continuously giving them low levels of antibiotic and slowly increasing it.
That's precisely what they did while investigating teixobactin, and they didn't see any resistance develop:
All of the comments are by armchair biologists about how the scientists are wrong and all bacteria strains will become resistant to it in 2 days.
But anyways, if it is an issue, why can't we just require antibiotics be taken intravenously? The vast majority of bacteria exposed to antibiotics are in your digestive system and that is where resistance develops. Or at least that's how I understand it.
IV antibiotics generally mean hospital, which generally means severe life-threatening infection.
Outpatient IV antibiotics are done but it's complicated and carry further risk of infection through having a line in situ for long periods of time.
IV antibiotics do have an effect on gut bacteria as well, it's not as simple as just not giving oral;
additionally (and, perhaps the crux of the issue) is that gut bacteria exposure to antibiotics is not how resistance develops; and certainly aren't the main problem.
It is the more common infective agents that cause the problems - Gram positive organisms (Strep Viridians, Staph Aureus etc) that usually enter from cuts or abscesses and, in the immunocompromised, cause significant disability.
>IV antibiotics do have an effect on gut bacteria as well, it's not as simple as just not giving oral;
How so? And more importantly how much antibiotics make it to the gut, vs if you take it orally? I would guess it would be a lot less.
>It is the more common infective agents that cause the problems
I know that, but as I understand it the resistance first evolves in gut bacteria, then spreads through horizontal gene transfer. Wikipedia cites this as the main cause of antibiotic resistance: https://en.wikipedia.org/wiki/Horizontal_gene_transfer
> How so? And more importantly how much antibiotics make it to the gut, vs if you take it orally? I would guess it would be a lot less.
I have no idea what figure or percentage it would be, but for most common antibiotics which end up distributed in total body water, there will be a component that leaks into the gut through capillary action; if it is metabolised in the liver then a proportion of it will end up in bile (if fat soluble) and then enter the gut that way; either itself or a metabolite of it - it would be impossible for me to quantify and likely depends on many many factors such as molecular weight, structure and a host of other features.
Patients on IV antibiotics develop diarrhoea from IV antibiotics at a similar rate (from what I have experienced) to those on orals. hence it undoubtedly kills bacteria in a similar fashion.
And we use IV antibiotics to kill bad infections of the gut. So whatever the mechanism, if I have elucidated it or simply done some hand-waving, it clearly affects it significantly.
The only instance of antibiotic use that touches on what I feel you are pushing for is the use of oral vancomycin (It is almost always IV) for severe bacterial infections of the gut - we use it oral because it is not absorbed systemically (as opposed to other specifically oral antibiotics) so doesn't cause systemic effects.
> then spreads through horizontal gene transfer.
Sure. But if you look at how they tested this particular antibiotic for the ability to develop resistance, they exposed TB and Staph to sub-theraputic doses for 27 days, or (for Staph) or 810generations (assuming a rough rate of division somewhere around 40 min to 1 hr in ideal conditions). An epic number of cell divisions if you work it out (and I can't).
The commonly accepted knowledge, as far as I understand it and as far as I have been taught it, whether or not bowel bacteria have a significant role to play or not, is that exposure of antibiotics to sub-lethal doses for long periods of time promote the survival of strains that have a competitive advantage against the agent in use, which over time allows the strain to survive in otherwise-lethal doses, and that gene becomes incorporated into a plasmid and then ends up spreading to every other organism capable of horizontal gene transfer.
Anyway, I am at home and not going to see the next MD, PhD in Infectious Diseases until tomorrow but when I do I will ask him and reply here. So, check back in 24 hours if you're interested
On the off-chance that you read this I apologise for not delivering, I wasn't able to speak to ID but will on Monday so if this thread is locked by then then shoot me an email
Don't assume everyone on here is an "armchair biologist".
There are several problems with IV antibiotics, some of which have been outlined in other comments:
1. It involves an IV. This means a hospital - that's both expensive for all involved, and the presence of an IV is in and of itself a risk for bacterial infection. Not all antibiotics kill all bacteria.
2. "The vast majority" = / = the ones experiencing resistance that are of clinical concern. C. difficile lives in your gut. MRSA on the other hand can live on your skin, and colonize your nasal passages. Both, additionally, cheerfully live on surfaces for quite some time (really quite some time for C. difficile).
3. IV antibiotics can reach your gut - some are excreted into the intestines. Metronidazole is, vancomycin isn't for example. And beyond that, much of the concern is with active infections, which are very likely not in your gut for many diseases, in contrast to just the background of your intestinal flora.
4. You're asserting that antibiotics reaching your gut from an IV would arrive in low doses. That's a good thing for promoting the development of resistance, not a bad thing, from the bacteria's perspective.
> “It should be used, if it gets successfully developed, as broadly as possible, because it is exceptionally well-protected from resistance development,” said Kim Lewis, one of the study’s authors and a professor at Northeastern University in Boston. Lewis estimated that it may take more than 30 years for bacteria to become resistant to teixobactin. He is also a co-founder of NovoBiotic Pharmaceuticals LLC, which is developing the drug.
I'd much rather get two or three more that all use different mechanisms, and use them as a cocktail.
Let the bugs try to develop 3 different kinds of resistance at once.
Multiple antibiotics often carry fairly serious medical risks. "Cured of your infection" is somewhat less heartening when we boxed your kidneys doing it.
Considering how many bacteria are out there, and how frequently many of them multiply, even a one in a quadrillion chance of a mutation providing a resistance benefit is barely a speed-bump in evolutionary terms. Their "thirty year" claim is a best guess, but as this is entirely random, it could be three hundred, and it could be three.
Remember there's about 10^14 bacterial cells in the average human body, ten times the number of human cells. Everyone's a big petri dish. If you killed all but one in a billion you'd still have a whole bunch left.
Can anyone clarify the core causes of antibiotic resistance over the last several decades?
I've heard the following causes, but I cannot substantiate them:
[1] Improper patient usage. Primarily, not taking the prescribed dosage long enough to eradicate all of the target bacterium, leaving (enough) survivors to meaningfully propagate their resistance. Typical to the "Hey I think my sinus infection is gone already! Adios remaining pills."
[2] Improper targeting. A functional antibiotic used on the wrong type of bacterium, or even usage against viruses.
Are there any others? Are my [1] and [2] debunked?
1. This is a major problem - patients start feeling better and discontinue therapy, which promotes resistance, save partially consumed prescriptions for "if this happens again", etc.
2. This is also a thing - broad spectrum antibiotics, difficulty in diagnosing, patients wanting something even if their infections are viral, etc. all lead to mistargeting of antibiotics for a number of reasons. Antimicrobial stewardship has become a major part of hospital infection control.
3. The widespread use of antibiotics in livestock. The agricultural use of antibiotics is staggering
"patients wanting something even if their infections are viral"
What the market needs is a placebo anti-biotic. One thats totally wasted by resistance so it won't hurt anything, and is reasonably cheap. Give it some nasty digestive system "effects" as a special gift to patients dumb enough to demand a pill against medical advice. Something that is, in fact, an antibiotic, so when they go home and look it up on wikipedia they don't freak out when they find out what a sucrose pill is. Maybe a homeopathic dose of it, so counter-reactions are rare and minimal.
Medical ethics are also very patient focused - it's hard to deal with situations that are good for this patient but bad for hypothetical future patients.
The mention of the "25 year discovery drought" made me think about this documentary I saw once about bacteriophages ("viruses that infect and replicate within bacteria") [1].
I don't remember the specific documentary but here is a wikipedia link [2] "Although extensively used and developed mainly in former Soviet Union countries circa 1920, the treatment is not approved in countries other than Russia and Georgia."
I think we'll be seeing more research like this in the future, where we develop drugs by mimicking nature instead of starting from scratch in the lab. Nature has had a few millions of years more to build and test things.
Nature (at least in terms of natural antibiotic sources like fungi and bacteria) also has a relatively quick turnaround in terms of adaptation.
Ultimately, developing antibiotics is a cat-and-mouse game, and eventually nanotech will render it archaic, but in the mean time the more we can do to be responsive and quick to adjust, the better, and that means new antibiotics.
I do worry about this "30 year projection" and what that's based on. Is that a historical norm?
I think nanotech will bring about it's own problems.
What we should be doing is addressing the cause of antibiotic resistance in the first place, namely the overprescription of antibiotics, and their improper use in industrial farming.
The over-prescription of antibiotics isn't the cause of antibiotic resistance, it's the cause of accelerated antibiotic resistance.
Which for all practical purposes might be the same thing, if we're talking 80 years versus 30 years for propagation of resistance.
Nanotech will be a very, very arduous and slow process. "Its own problems" is putting it lightly. People will die due to nanotech approaches to anti-pathogenics, no question about it. We're talking about programmable biology, something will go wrong.
The biggest problem is what happens when we've eliminated human pathogens? What happens when we've extended the average life expectancy by 10 years - after all, many cancers are caused by pathogens. What happens to the ecosystem when herpesviridae is effectively gone? What are the side effects, the unintended consequences?
The 30 years guess is based on the history of vancomycin, which like teixobactin was isolated from a soil bacteria. They presume, based on multiple similarities and things like teixobactin producing bacteria not having innate immunity to it except for not having cell walls, that it could have a similar period of freedom from resistance development. And if their thesis and what they think they know about it is correct, it could have an even better experience.
But least awful iterated thousands of times eventually leads to either "the best" or comparable to "the best." Not always the most efficient route, but largely dependable at scale.
A very interesting submission about the big medical news story of the day. The news suggests that we can all enjoy significant gains in finding effective treatments for dangerous infections. The era of antibiotics is probably not over yet, by a long way.
As noted in another comment, the underlying Nature article is up on the World Wide Web, [after edit:] and now shared to all of us by a subscriber who posted a subscriber's-sharing link in this thread.[1] I searched for some other news stories about this preliminary research finding to link to others based on independent reporting as well as the authors' press release and the Nature article. I found a story in Financial Times[2] reporting, "Teixobactin quickly kills Gram-positive bacteria, which are prominent in discussions of antibiotic resistance, including Clostridium difficile,Mycobacterium tuberculosis and Staphylococcus aureus.
"Neil Woodford, head of the antimicrobial resistance unit at Public Health England, commented:
"'The rise in antibiotic resistance is a threat to modern healthcare as we know it, so this discovery could potentially help to bridge the ever increasing gap between infections and the medicines we have available to treat them.'
"But Prof Woodford added: 'Although it is a step forward, this new discovery would not be suitable for treating infections caused by E. coli,Klebsiella or other Gram-negative bacteria.'"
The Washington Post reports,[3] "But all good things must eventually come to an end.
"'They didn't find resistance in a couple of simple tests, so it won’t happen in a minute, but there is no compound on this planet that bacteria will not develop resistance to,' Said Richard Novick, an NYU Langone Medical Center professor who wasn't involved in the study. 'But it would certainly happen more slowly with this one.'
"And unfortunately, the drug's genius mechanism is also its biggest flaw. It can only target so-called gram-positive bacteria, like staph, strep, and TB, because they're unprotected once their cell wall starts to break down. Gram-negative bacteria like E. coli and the organisms that cause many sexually transmitted infections have an outer membrane that Teixobactin can't penetrate. That's probably a safety mechanism built-in by the gram-negative bacteria that created Teixobactin in the first place."
That expert also comments that he would strictly limit application of this antibiotic at first to hospital settings, and that would be my policy recommendation too, to reduce the chance of producing selection pressure for resistant strains of bacteria. But this does look like it could be a big advance in clinical treatment of gram-positive bacterial infections resistant to other antibiotics.
The reporting in The Scientist,[4] already linked by an earlier participant, includes a comment on the laboratory technique used to find the microorganism that produces this new antibiotic: "'This is a very clever technique,' added Robert Austin, a physicist at Princeton University who studies the evolution of microbes and was not involved in the current study. 'The bacteriology community needs to get away from culturing bacteria on agar plates, because this will not lead to new antibiotics.'" That's a familiar principle in science: look in a new place, and make new discoveries.
The reporting in The Guardian[5] picks up on that idea in the words of another expert: "'What most excites me is the tantalising prospect that this discovery is just the tip of the iceberg,' said Mark Woolhouse, professor of infectious disease epidemiology at the University of Edinburgh. 'It may be that we will find more, perhaps many more, antibiotics using these latest techniques.'"
It's very likely that there are more antibiotics yet to be discovered, because all microorganisms live in a world full of other microorganisms, and haphazard adaptation to that environment must have produced selection pressure for many microorganisms to produce natural chemicals ("antibiotics") that kill off other kinds of microorganisms. Putting those chemicals into human bodies applies human knowledge to take advantage of the variety of life that has arisen from evolution.
I'm skeptical that this is a good thing given how the profit motive motivates people to "externalize" side effects; Environmental damage from antibacterial soaps, disrupting natural biological processes, disease-resistant bacteria, are a few effects.
> Scientists have discovered an antibiotic capable of fighting infections that kill hundreds of thousands of people each year
Given it's potential as a medicine, the media will hype it into public consciousness. Marketers & Entrepreneurs will use this social inertia to sell it in places where it is dangerous to use. The FDA has a history of revolving doors with big pharma & playing loose in pandering to corporate interests, at the expense of the public & environment.
I'm merely presenting a minority view here on Hacker News. It's good to have all your t's crossed and i's dotted.
"...strikes multiple targets, including cell walls...Since the lipid structures it attacks don’t evolve as quickly as frequently mutating proteins, it may take the bacteria longer than usual to develop a survival tactic."
Proteins change often and quickly, but basic cell structures may take longer or never adapt.
But I'm not a pathobiologist, I just play one on the Internet