Choose your metaphor, but it sounds like great news

July 18, 2020 1:23 PM

"Poison is lethal all on its own - as are arrows - and together, they can take down the strongest opponents." A new dual mechanism antibiotic being developed promises to be highly effective, safe, and immune to resistance.

Princeton study in the journal Cell

posted by blue shadows (34 comments total)

In a just world, this rights to this molecule would be given to all for the good of humanity.
posted by seanmpuckett at 1:34 PM on July 18, 2020 [8 favorites]

Srsly. It's not like decent people are unprecedented in human history.

An interviewer once inquired about the ownership of the polio vaccine patent, to which Salk famously answered, “Well, the people, I would say. There is no patent. Could you patent the sun?” It was this spirit of humanism in combination with his astounding accomplishments in virology and vaccine development that have permanently etched Salk into the annals of medical history.

posted by j_curiouser at 1:51 PM on July 18, 2020 [21 favorites]

This is great. Though I’m fairly sure that bacteria will eventually develop resistance to this as well. Still, very exciting.
posted by brevator at 3:41 PM on July 18, 2020 [1 favorite]

This is really great. The HIV “cocktail” uses several antivirals in tandem, the idea being that the chance of simultaneous resistance mutations is vanishingly small. But this one compound has two effective mechanisms that a bacterium must overcome at once. If that weren’t enough, it’s effective against Gram positive and negative! This really could be a game changer.
posted by sjswitzer at 3:47 PM on July 18, 2020 [7 favorites]

If we don't find something that works, we'll be back in the pre-antibiotic era soon, and I don't think anyone wants to go there.
posted by hippybear at 4:35 PM on July 18, 2020 [6 favorites]

TIL Typical antibiotics research involves finding a molecule that can kill bacteria, breeding multiple generations until the bacteria evolve resistance to it, looking at how exactly that resistance operates, and using that to reverse-engineer how the molecule works in the first place.

Whoa.
posted by skyscraper at 4:43 PM on July 18, 2020 [24 favorites]

That is some serious 21st century research right there. Go go go! for the people doing that work!
posted by hippybear at 5:02 PM on July 18, 2020 [1 favorite]

Any idea who'll own it? In the funding section I see mention of NIH, NSF, and NCI, but also the "Princeton DFR Innovation Funds for New Ideas in Science". What does that mean in terms of patent and IP rights?

"It is nearly 1,000 times more potent against bacteria than human cells, making it a promising antibiotic." Any idea what that means in terms of side effects? Is that "don't have to worry about it at all" or "has to be carefully dosed so we don't kill you" or something in between?
posted by clawsoon at 6:15 PM on July 18, 2020

Well, once the antibiotic agent has killed off the bacteria, we'll send in the gorillas to kill off the antibiotics.
posted by delfin at 6:45 PM on July 18, 2020 [11 favorites]

Universities are pretty aggressive about their patent rights these days. I'd imagine Princeton will own the patent, probably spinning it off into a biotech IP arm of some sort.
posted by biogeo at 6:58 PM on July 18, 2020 [6 favorites]

CIPRO-resistant staph is a real, daily thing here in Key West, where even a scratch can turn into a sci-fi level flesh-eating nightmare overnight. The only way around it is to hit it with a mix of old and new antibiotics and sulfa drugs until one or a combination of them nails it, and they are really not good for your system either. Bactrim, anyone?
Because I realize we're the privileged edge of the tropics here, I pray that this will be humanely distributed by Princeton to places that have it a lot worse than we do, and not held for ransom by a drug manufacturer.
posted by halfbuckaroo at 7:02 PM on July 18, 2020 [8 favorites]

JFC. Another sciencedaily hypefest. This is a neat proof-of-principle mechanism, but this is an early report in Cell with zero mention of tox studies beyond mammalian cell studies and a quick run through some mice - did their liver get completely borked? No? We're all good then!

Tox studes are the graveyard of antibiotics (and many other drugs) for all but the most lethal of infections. This compound looks like a greasy nucleoside (the kind of thing that your body uses to replicate DNA and RNA) and therefore has a really broad chance of being nasty. Many many nucleoside drugs die in tox.....


I pray that this will be humanely distributed by Princeton to places that have it a lot worse than we do, and not held for ransom by a drug manufacturer.

sigh. thats not how this works. that's not how any of this works. if it makes it through the more serious animal tox screens that cost millions, it will cost in excess of $20m in trials (probably more like $50m) before this gets to a person who's not dying of a lethal infection and gets an emergency use waiver.

that's assuming that this drug is in fact suitable. this is likely a lead compound that will need another 5 years of fulltime work (see:10s of millions more) to optimize its pharmacokinetics and tox before it makes it to phase I.....

I say this as a lefty academic: drugs don't just pop out of academic groups ready to be used in humans....even rich groups out of princeton. it costs hundreds of millions of dollars of real, non-negotiable work by thousands of people over multiple years to develop safe drugs, and that money and manpower has to come from somewhere.

under capitalism as practiced, that's drug companies. thats' why we need to nationalize research.....a la the welcome trust. but that's a different topic.......
posted by lalochezia at 8:00 PM on July 18, 2020 [69 favorites]

Speaking as someone who’s had more antibiotics than hot meals, this is incredibly exciting.
posted by The Underpants Monster at 8:14 PM on July 18, 2020 [2 favorites]

under capitalism as practiced, that's drug companies.

You've just diagnosed your ailment right there.
posted by JackFlash at 9:25 PM on July 18, 2020 [4 favorites]

Seconding what lalochezia said, this is a long, long way from being a drug.
They talk about therapeutic index in cell lines, but that’s only very remotely related to whole-organism toxicology, and they completely omit any toxicology information about their tiny mouse study - at the very least you’d usually look at the mice for subjective signs of toxicity then sacrifice and do a superficial necropsy. Their prototype drug (the SCH library compound) inhibits growth in various immortalised lines - quite possibly by a nucleotide-analog mechanism as lalochezia hints at - and that activity may well not be completely gone in the modified compound.
Their preliminary pharmacokinetic data shows a long metabolic half-life, which is good in a sense, but also means the drug is not easily metabolised in the liver, and things that are hard to metabolise can be problematic if the eventual process is via ring-opening.
I could go on - but to use a analogy to the phasing of clinical trials, this compound isn’t even really at the Phase I stage _in animals_... That said, it’s an interesting lead - even if it totally fails for toxicological or pharmacological reasons it’ll serve as the structural basis for other investigational compounds.
posted by memetoclast at 9:45 PM on July 18, 2020 [8 favorites]

This does indeed sound like great news. The researchers mention that the "poison arrow" approach that their drug follows - could open up the way to other compounds that take a similar approach. They also mention that the drug was initially pretty lethal to human cells as well a bacteria - but that they were able to fine tune it to become more selective. Again - I guess others could follow the same development route maybe?

"It is nearly 1,000 times more potent against bacteria than human cells" - That sounds promising - but I guess the baseline would be to understand how damaging ordinary antibiotics are to human cells.
posted by rongorongo at 11:46 PM on July 18, 2020 [2 favorites]

> They also mention that the drug was initially pretty lethal to human cells as well a bacteria - but that they were able to fine tune it to become more selective. Again - I guess others could follow the same development route maybe?

I'm guessing, by how they don't brag about it, that they didn't invent the methods used to reduce human cell mortality. So probably this is already done elsewhere?

It's worth pointing out that the ScienceDaily "article" was largely written by a science writer at the Princeton Office of Communications: it's a press release, so of course it uses the most optimistic language possible.

(the kind of thing that your body uses to replicate DNA and RNA) and therefore has a really broad chance of being nasty.

I was wondering how the heck that wasn't a dealbreaker. I guess it just didn't find its way inside human cells, but if it (or a nasty one of its metabolites) did, game over?

And like, how does one manufacture an organic that destroys DNA and RNA?
posted by pwnguin at 12:59 AM on July 19, 2020

This compound looks like a greasy nucleoside

Appreciate your anti-hype contribution to this thread, but are you looking at the right structure? It's not a nuc.
posted by mark k at 7:52 AM on July 19, 2020 [3 favorites]

Is is a flat aromatic amine (either a quinazoline or indole, if you like that kind of nomenclature BS) that looks like a nucleoside that has two relatively hydrophobic groups protruding from it (cyclopropyl and isopropyl-benzyl). But you're correct, it's not an actual nucleoside.
posted by lalochezia at 8:14 AM on July 19, 2020 [4 favorites]

This is great. Though I’m fairly sure that bacteria will eventually develop resistance to this as well.

I’m imagining bacteria taking a cue from history and creating the ironclad. Staphylococcus monitoreus, Merrimackus gonorrhoeae, etc.
posted by Thorzdad at 8:51 AM on July 19, 2020 [2 favorites]

Guessing lalochezia would know more about this than I do but to me that structure kind of looks like some kind of mutant folate, which makes sense given that they have good evidence one of its targets is DHFR. I’m on my phone so I can’t search through the paper but I’d be curious whether they tried to get resistant mutants to their compound in trimethoprim-resistant bugs since that drug also targets DHFR and resistance is not uncommon. If the reason they gave for not getting resistance is that you need to develop mutations against two separate things, trying it in a trimethoprim resistant background should help. Again without reading the paper super closely, I’m getting the sense that one of the real achievements here is in the methods they developed or repurposed to find a drug MOA in the absence of any help from genetic screens.
posted by en forme de poire at 3:36 PM on July 19, 2020 [2 favorites]

Is is a flat aromatic amine (either a quinazoline or indole, if you like that kind of nomenclature BS) that looks like a nucleoside

So this has been a big part of my professional life: Nuc analogs are a class of drug and this isn't one. There is no sugar and no sugar mimetic. The 'northwest' heterocycle (in the wiki drawing) is indeed a pyrimidine, which could if not connected to two other rings make a nuc's base, sure. But that doesn't mean much--probably more than half of modern small molecule drugs have something in that ballpark, including for example most kinase inhibitors. It might be toxic but not because it's getting picked up by a polymerase and messing with the replication machinery.
posted by mark k at 10:29 PM on July 19, 2020 [6 favorites]

As somebody else who works in drug development I would just like to say for the average layperson, the time to be excited about a drug is when it is approved by the FDA after a successful phase 3 and not a second before. (Even then, wait as long as you can before taking anything that has a novel structure or mechanism of action.)
posted by benzenedream at 10:42 PM on July 19, 2020 [7 favorites]

As someone allergic to sulfa and cipro, I am interested in where this research goes. Albeit, understanding it could be a decade before anything comes to market.
posted by SecretAgentSockpuppet at 2:20 AM on July 20, 2020

So this has been a big part of my professional life: Nuc analogs are a class of drug and this isn't one. There is no sugar and no sugar mimetic. The 'northwest' heterocycle (in the wiki drawing) is indeed a pyrimidine, which could if not connected to two other rings make a nuc's base, sure. But that doesn't mean much--probably more than half of modern small molecule drugs have something in that ballpark, including for example most kinase inhibitors. It might be toxic but not because it's getting picked up by a polymerase and messing with the replication machinery.


fair enough. i should have used the words "nucleobase" rather than "nucleoside", but mark k's right about similar flat aromatic components being of being large part of many many successful drugs. sometimes the map is not the territory even if one of the signposts is quite realistic, and I got fixated on that (flat-pyrimidine-like aspect) of the structure.
posted by lalochezia at 4:49 AM on July 20, 2020 [1 favorite]

thats' why we need to nationalize research

Internationalize please. I work in an area that right now is almost completely funded by my government, even to the effect of US federal agencies receiving primary funding from the government of Canada. However, less than a decade ago, the situation was almost exactly reversed, and we were the ones accepting US and European and Chinese funding. Internationalization is a major defense against the vicissitudes of radical popularisms.
posted by bonehead at 6:04 AM on July 20, 2020 [1 favorite]

Internationalize please

"if you wish to make an apple pie from scratch, you must first invent the universe."

if you wish for equitable healthcare processes for the world's populaces, you must reinvent pan-global governmental structures. sigh.
posted by lalochezia at 8:11 AM on July 20, 2020

> if you wish for equitable healthcare processes for the world's populaces, you must reinvent pan-global governmental structures. sigh.

Why are you sighing? This is what India and many African countries have been saying for years.

On another topic: one terrifying thing I haven't seen mentioned yet is whether this molecule could harm beneficial bacteria. Beneficial bacteria's span is much larger than human guts alone - without them, the world as we know it wouldn't exist.
posted by splitpeasoup at 9:43 AM on July 20, 2020

I'm sighing because it's very fucking hard and racist nationalist governments, including Modi's are making it harder.
posted by lalochezia at 10:03 AM on July 20, 2020

splitpeasoup, not my field but I'm absolutely sure it will harm beneficial bacteria. It's pretty much impossible to imagine a broadly active, low resistance antibiotic that would not. If there is a widespread mechanism bacteria have to avoid it harming you, the bacteria can "learn" it (from mutation or gene swapping with resistant bacteria.)

Sparing use saved for important cases is still going to be the critical procedure to avoid additional damage.
posted by mark k at 7:55 PM on July 20, 2020

Stupid person question: how similar is an antiviral to an antibiotic?

And how similar is an anti-virus vaccine to an anti-bacteria vaccine?

Would they affect each other much at all? I've had anti-virus vaccines but all ages ago, and don't remember any real adverse reactions to them related to, say, my gut bacteria, which, say, oral antibiotics just ravage.

Literal stupid person question. Lack of knowledge has me feeling they should be different enough? But maybe not?
posted by hippybear at 8:30 PM on July 20, 2020

Those aren't stupid questions at all. I'm not an expert in this but I'll give a stab at it. Understanding the difference in the drugs requires thinking about the difference between viruses and bacteria, and between a drug to treat an infection and a vaccine which prevents infection.

As disease-causing agents, viruses and bacteria have one extremely important difference. Bacteria are independently living cells, with their own metabolism and an independent ability to replicate themselves. You can stop bacterial infections by attacking their cell membranes directly to damage or destroy them, by interfering with their metabolism to stop them from being able to use energy or engage in some other critical process (which will kill them), or by interfering with their ability to reproduce (which will stall them for long enough for the body's normal immunity to catch up and take them out). Some bacteria are extremely difficult to target with certain antibiotics, e.g., due to specializations that protect the cell membrane from attack, or by using alternative metabolic pathways that aren't harmed by the drug. A so-called "broad-spectrum" antibiotic is one that targets a pathway or mechanism that is common to many different species of bacteria, often including the "good" bacteria that live in your gut, which is why these antibiotics can have side effects on your digestion. In addition to their effects on bacteria, many antibiotics also have other biological activity, which can also lead to side effects not directly related to their antibiotic activity.

By contrast, a virus is not an independently living cell, and has no metabolism [1]. This means that an antiviral drug has a lot fewer targets to attack. A virus replicates by adding its genetic material into a host cell, causing the host cell to manufacture the virus instead of its normal function, until it eventually dies and releases the new viral particles to infect other cells. Some viruses, called retroviruses, use RNA instead of DNA to encode their genomes, and this RNA needs to be converted into DNA before the cell can process it. Since this is not something that normally happens in human cells, the biochemical mechanisms involved in this process are one target for antivirals, and this class is specifically referred to as antiretrovirals. But many viruses use DNA so this pathway isn't available to target, and some antivirals just work by targeting more general mechanisms for DNA transcription. This of course can have a whole lot of side effects, because your body needs DNA transcription for all kinds of reasons, and partially shutting that down can do various bad things to you. But for a serious viral infection that can be worth it. There are probably antiviral drugs that target other pathways that may be more specific, but in general we have a lot fewer antiviral drugs than antibiotics, simply because there are a lot fewer targets to attack in the life cycle of a virus. This is why so many viral infections are basically untreatable aside from alleviating symptoms until the body is able to fight off the infection itself.

In contrast to antibiotics and antivirals, vaccines don't attack the infectious agent. They work instead by training the body's immune system to attack them. Each species or strain of bacterium and virus (and parasites for that matter) have proteins that are unique (or nearly unique) to them, meaning that if those proteins are present it is a sure sign of infection by that agent. To identify them, your immune system produces antibodies, which are chemicals that are capable of binding with some of these proteins. A protein that an antibody is capable of recognizing is called an antigen. When an antibody interacts with an antigen on a bacterium or viral particle, it "tags" it and initiates a cascade of effects that lets your immune system kill and clear out the offending pathogens. The immune system actually produces a truly immense variety of these antibody molecules, which in sum are capable of recognizing a potentially vast number of antigens, but only a fraction of these antibodies are produced in large enough quantities to initiate an immune response when a pathogen bearing the associated antigen causes an infection. So the first time your body encounters a pathogen, the immune system won't immediately be able to recognize it as such, and the bacterium or virus can cause a serious infection. But in the process, one of the various antibodies your body produces may interact with an antigen on the bacterium or virus, and that causes the immune system to basically identify that antibody as a useful one for finding pathogens, and dramatically ramp up its production. Thus the next time that pathogen gets into your system, your body immediately recognizes it and mounts an immune response, preventing it from being able to cause an infection, or at least limiting the scope of the infection. This is a highly simplified description but captures the essence of what happens. [2]

Vaccination just skips the initial infection step, and goes straight to the antigen-presentation step. This can happen by using, for example, killed bacteria, or disabled viruses, which are incapable of causing an infection but which still possess the antigen molecules that the immune system can recognize and learn to attack. In some cases you can identify a specific antigen protein and use that as the vaccine. Vaccines can have side effects due to provoking an overly strong immune response (this is probably the most common) or due to a direct action of one or more components of the injected agent, or due to an adverse reaction to one of the other components of the vaccine (e.g., stabilizers and preservatives).

Note that in my discussion of vaccines I didn't differentiate between viruses and bacteria. Since I'm not an immunologist I'm not sure if there's a more subtle, systematic difference between vaccines for viruses versus those for bacteria, but at least at the level of basic principle they work exactly the same: train the body to recognize a particular antigen as foreign, so it will mount an attack when it sees it.

So armed with all that, to your specific questions. How similar are antivirals and antibiotics? They are generally pretty different, because antibiotics can target biochemistry that is unique to bacteria, while antivirals often have to act on biochemistry that is also part of normal human cell function. How similar are vaccines to viruses versus those to bacteria? Broadly speaking pretty similar, though there may be complications beyond my level of expertise that others can comment on.

Your question of "would they affect each other much" is probably the hardest to answer. In general I'd say there's no specific reason why they have to, but in practice biology is very messy. Specifically, antibiotics can have biological activity not related to their antibiotic activity, and antivirals can affect a whole host of cellular processes. Very likely this is something that would need to be discovered on a case-by-case basis.

[1]: There are always exceptions in biology and I think I recall reading about a discovery of metabolic activity in some viruses recently but this is the exception and may apply only to giant viruses which as far as I know aren't disease-causing in humans.

[2]: One of the sad ironies of the anti-vaccine movement is that there's significant overlap with people who are proponents of homeopathic medicine. Homeopathy is the idea that a small quantity of something that makes you sick can heal you from the same sickness. In general this is nonsense, except in the case of vaccination! Vaccines are literally the only type of homeopathy that actually works, yet homeopaths are often among the first to denounce vaccination.
posted by biogeo at 10:35 PM on July 20, 2020 [10 favorites]

I would just add to biogeo's nice explanation that chemicals such as antivirals and antibiotics often have effects on each other (usually by competing for some detoxification pathway), vaccines rarely do since they only activate a very targeted immune response rather than trying to shut down some aspect of metabolism.
posted by benzenedream at 2:31 PM on July 21, 2020 [4 favorites]

biogeo: you are generous with your time and knowledge, and I thank you for your response. That's excellent, and I feel much better informed now. Thanks!
posted by hippybear at 8:47 PM on July 21, 2020 [4 favorites]