This should be re-titled something like: with 200x longer sequences and making products without culturing, dirt can make antibiotic gold.
The two prospects:
Erutacidin, disrupts bacterial membranes through an uncommon interaction with the lipid cardiolipin and is effective against even the most challenging drug-resistant bacteria.
trigintamicin, acts on a protein-unfolding motor known as ClpX, a rare antibacterial target
The difficulty with bacterial DNA is that they have common elements and actively share DNA to boot. Sequencing only short sections make genome assembly unreliable. 200x longer sequences makes much more accurate genomes.
Then even if you find genes, we can't usually culture enough bacteria to make the product (typically instead injecting the sequences into bacteria we can culture). So being able to make the product without culturing the organism is key.
> So being able to make the product without culturing the organism is key.
No, it isn't. The article talks about using chemical synthesis, rather than using a biological platform to express the product via genes.
"To convert the newly uncovered sequences into bioactive molecules, the team applied a synthetic bioinformatic natural products (synBNP) approach. They bioinformatically predicted the chemical structures of natural products directly from the genome data and then chemically synthesized them in the lab. With the synBNP approach, Brady and colleagues managed to turn the genetic blueprints from uncultured bacteria into actual molecules—including two potent antibiotics."
Spoiler, I haven't read the article, but my understanding is cardiolipin targeting antibiotics have failed in the past because our mitochondria are enriched for it. (Which makes sense here because the mitochondria are derived from ancient bacteria). I'm sure there is potential for optimization for medical applications, but we will have to be very careful for adverse effects.
Turns out the old saying, "Let the kids play and eat dirt," might’ve been right all along—who knew? All this time, they might've been giving themselves tiny doses of natural antibacterials without even realizing it.
One of the antibiotics targets a protein that is also essential in mitochondria, so it's not a good candidate for a drug. The other targets bacterial cell membranes and showed no resistance developing, which seems more promising.
Newly discovered potential antibiotics are actually pretty common, and they would be critical to solving the antibiotic-resistance menace. But no major new families of antibiotics have been brought to market since about 01962, although a dozen or so families were discovered over the previous 20 years. (Or, maybe one new family was.) That was when drug regulation changed dramatically in the US with https://en.wikipedia.org/wiki/Kefauver%E2%80%93Harris_Amendm..., for example requiring clinical trials to provide evidence that drugs were effective, rather than just safe. It's also when they started outlawing recreational drugs; the Single Convention on Narcotic Drugs wasn't until 01961, and it didn't cover amphetamines, downers, or psychedelics.
Because so much of 20th-century drug research happened in the US (because the US had capitalism) the clinical-trials requirement and the Drug War there had an outsized effect, and other countries copied them afterwards.
One particular case that I studied was Zasloff's "magainin": https://en.wikipedia.org/wiki/Magainin which was denied licensing even though the clinical trials found that it was both safe and effective. The problem was that it wasn't more effective than the existing standard of care; it was only equally effective.
It seems certain that the Kefauver–Harris Drug Act has prevented innumerable cases of useless or harmful drugs from being marketed. But, looking at the history of drug development, it also seems clear that the rapid drug development in the decades up to 01962 virtually halted at that time, and the absence of the drugs that would have been discovered since then has surely killed many more people than the inadvertent use of harmful drugs ever could have.
>The problem was that it wasn't more effective than the existing standard of care; it was only equally effective.
That is misleading. When a clinical trial is designed for non-inferiority, it doesn't say anything about being superior or equal. Just as legally, a defendant is either guilty or not guilty - there is no legal adjudication of being "innocent".
These drugs are not comparable (different stability profiles, different mechanisms of action, etc) and to say they're equal is highly misleading.
>and the absence of the drugs that would have been discovered since then has surely killed many more people than the inadvertent use of harmful drugs ever could have.
There is no evidence that safety regulations have denied us some miracle drug. I don't want the FDA approving drug products that are harmful to the general population. You haven't made a good argument for "the greater good" besides a reference to magainin, a product for topical treatment of foot ulcers. There are thousands of known anti microbial peptides.
"There is no evidence that safety regulations have denied us some miracle drug."
Well, of course we don't know of a specific miracle drug they've denied us, because it isn't until after a drug is in wide use that you find out whether it's a miracle drug or not. But we can see that there were enormous numbers of miracle drugs in the 20 years immediately preceding the safety regulations, and almost none in the 63 years since then. There have definitely been some† but a very large slowdown is clearly evident if you look at the history. Most of even the important new drugs since then are slight variations on previously known molecules.
A reasonable inference from these observations is that safety regulations have denied us a lot of miracle drugs.
______
† zidovudine, Paxlovid, oral rehydration therapy, ivermectin, propofol, SSRIs, arguably buprenorphine, sildenafil, acyclovir, misoprostol, and ritonavir come to mind; and time will tell whether lovastatin and semaglutide belong on this list or with fen/phen and heroin.
My pet idea is that Western societies should prescribe antibiotics at random to a different tiny fraction of the elderly population each month / year.
People who suffer from unexplained / untreatable diseases like arthritis or MS might get some relief, while there would be an added pressure on the pharma industry to innovate in antibiotic development by accelerating the loss of existing antibiotic efficacy through the evolution of resistance.
Horrible idea antibiotics are not toys and have side effects. Don't use elderly people for experiments when they are the one group least able to handle this.
You want to cause current antibiotics to be less useful so pharma will invest more? Just allow generic versions.
If you want to pressure the pharma industry use laws.
Every major family of antibiotics has generic versions, and that is not resulting in the needed discovery. This is probably because the vast majority of the "investment" required is in compliance with regulations that didn't exist when the currently-widely-used antibiotics were discovered.
Some antibiotics do have a good enough safety profile that such occasional speculative use would be a good tradeoff. Elderly people are also the one group least able to handle infections! Others do not.
Look at the 1940s/1950s when some classic antibiotics were discovered. Pharma workers taking vacations overseas were asked to bring soil samples back to the lab. Great reading if you enjoy science history.
Some of the immunosuppressant drugs were discovered from bacteria in soil including Tacrolimus and Sirolimus. And Cyclosporine and Mycophenolate came from a fungus in soil.
I have a kidney transplant and use two of these medications daily.
Tacrolimus was discovered in 1987 by a Japanese team led by pharmacologist Tohru Kino; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.[45] It is produced by a soil bacterium, Streptomyces tsukubensis.[46] The name tacrolimus is derived from "Tsukuba macrolide immunosuppressant".[47]
When you study organic synthesis, these kinds of structures are the Holy Grail. Sometimes it takes dozens of steps, and an overall yield of just a few percent to make them synthetically.
There are millions on the lower bound of bacteria species we havn't identified, trillions on the upper bound. Unknown bacteria are literally everywhere, but the simple act of finding and sequencing them is nothing to be afraid of.
Meh, they came from the soil. It's always been here, just never seen by human eyes. That's true of lots and lots of bacteria though - we find new species pretty much every single time we take a stomach sample from someone, let alone random forest soil.
Many bacteria have commensal lifestyles —- scientists don’t feel in control if they can’t culture bacteria in isolation but in nature many bacteria aren’t metabolically complete and son’s live in isolation.
This should be re-titled something like: with 200x longer sequences and making products without culturing, dirt can make antibiotic gold.
The two prospects:
Erutacidin, disrupts bacterial membranes through an uncommon interaction with the lipid cardiolipin and is effective against even the most challenging drug-resistant bacteria.
trigintamicin, acts on a protein-unfolding motor known as ClpX, a rare antibacterial target
The difficulty with bacterial DNA is that they have common elements and actively share DNA to boot. Sequencing only short sections make genome assembly unreliable. 200x longer sequences makes much more accurate genomes.
Then even if you find genes, we can't usually culture enough bacteria to make the product (typically instead injecting the sequences into bacteria we can culture). So being able to make the product without culturing the organism is key.
> So being able to make the product without culturing the organism is key.
No, it isn't. The article talks about using chemical synthesis, rather than using a biological platform to express the product via genes.
"To convert the newly uncovered sequences into bioactive molecules, the team applied a synthetic bioinformatic natural products (synBNP) approach. They bioinformatically predicted the chemical structures of natural products directly from the genome data and then chemically synthesized them in the lab. With the synBNP approach, Brady and colleagues managed to turn the genetic blueprints from uncultured bacteria into actual molecules—including two potent antibiotics."
Isn't that saying the same thing a different way? Chemical synthesis is a way to make the assumed molecular product without culturing the organism.
Spoiler, I haven't read the article, but my understanding is cardiolipin targeting antibiotics have failed in the past because our mitochondria are enriched for it. (Which makes sense here because the mitochondria are derived from ancient bacteria). I'm sure there is potential for optimization for medical applications, but we will have to be very careful for adverse effects.
Turns out the old saying, "Let the kids play and eat dirt," might’ve been right all along—who knew? All this time, they might've been giving themselves tiny doses of natural antibacterials without even realizing it.
Is there a good explainer of the challenges of growing dirt based bacteria in the lab?
The paper:
https://www.nature.com/articles/s41587-025-02810-w
One of the antibiotics targets a protein that is also essential in mitochondria, so it's not a good candidate for a drug. The other targets bacterial cell membranes and showed no resistance developing, which seems more promising.
Newly discovered potential antibiotics are actually pretty common, and they would be critical to solving the antibiotic-resistance menace. But no major new families of antibiotics have been brought to market since about 01962, although a dozen or so families were discovered over the previous 20 years. (Or, maybe one new family was.) That was when drug regulation changed dramatically in the US with https://en.wikipedia.org/wiki/Kefauver%E2%80%93Harris_Amendm..., for example requiring clinical trials to provide evidence that drugs were effective, rather than just safe. It's also when they started outlawing recreational drugs; the Single Convention on Narcotic Drugs wasn't until 01961, and it didn't cover amphetamines, downers, or psychedelics.
Because so much of 20th-century drug research happened in the US (because the US had capitalism) the clinical-trials requirement and the Drug War there had an outsized effect, and other countries copied them afterwards.
One particular case that I studied was Zasloff's "magainin": https://en.wikipedia.org/wiki/Magainin which was denied licensing even though the clinical trials found that it was both safe and effective. The problem was that it wasn't more effective than the existing standard of care; it was only equally effective.
It seems certain that the Kefauver–Harris Drug Act has prevented innumerable cases of useless or harmful drugs from being marketed. But, looking at the history of drug development, it also seems clear that the rapid drug development in the decades up to 01962 virtually halted at that time, and the absence of the drugs that would have been discovered since then has surely killed many more people than the inadvertent use of harmful drugs ever could have.
>The problem was that it wasn't more effective than the existing standard of care; it was only equally effective.
That is misleading. When a clinical trial is designed for non-inferiority, it doesn't say anything about being superior or equal. Just as legally, a defendant is either guilty or not guilty - there is no legal adjudication of being "innocent".
These drugs are not comparable (different stability profiles, different mechanisms of action, etc) and to say they're equal is highly misleading.
>and the absence of the drugs that would have been discovered since then has surely killed many more people than the inadvertent use of harmful drugs ever could have.
There is no evidence that safety regulations have denied us some miracle drug. I don't want the FDA approving drug products that are harmful to the general population. You haven't made a good argument for "the greater good" besides a reference to magainin, a product for topical treatment of foot ulcers. There are thousands of known anti microbial peptides.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7937881/
"There is no evidence that safety regulations have denied us some miracle drug."
Well, of course we don't know of a specific miracle drug they've denied us, because it isn't until after a drug is in wide use that you find out whether it's a miracle drug or not. But we can see that there were enormous numbers of miracle drugs in the 20 years immediately preceding the safety regulations, and almost none in the 63 years since then. There have definitely been some† but a very large slowdown is clearly evident if you look at the history. Most of even the important new drugs since then are slight variations on previously known molecules.
A reasonable inference from these observations is that safety regulations have denied us a lot of miracle drugs.
______
† zidovudine, Paxlovid, oral rehydration therapy, ivermectin, propofol, SSRIs, arguably buprenorphine, sildenafil, acyclovir, misoprostol, and ritonavir come to mind; and time will tell whether lovastatin and semaglutide belong on this list or with fen/phen and heroin.
My pet idea is that Western societies should prescribe antibiotics at random to a different tiny fraction of the elderly population each month / year.
People who suffer from unexplained / untreatable diseases like arthritis or MS might get some relief, while there would be an added pressure on the pharma industry to innovate in antibiotic development by accelerating the loss of existing antibiotic efficacy through the evolution of resistance.
Horrible idea antibiotics are not toys and have side effects. Don't use elderly people for experiments when they are the one group least able to handle this.
You want to cause current antibiotics to be less useful so pharma will invest more? Just allow generic versions.
If you want to pressure the pharma industry use laws.
Every major family of antibiotics has generic versions, and that is not resulting in the needed discovery. This is probably because the vast majority of the "investment" required is in compliance with regulations that didn't exist when the currently-widely-used antibiotics were discovered.
Some antibiotics do have a good enough safety profile that such occasional speculative use would be a good tradeoff. Elderly people are also the one group least able to handle infections! Others do not.
It's a promising idea, but probably wouldn't help with drug discovery.
Look at the 1940s/1950s when some classic antibiotics were discovered. Pharma workers taking vacations overseas were asked to bring soil samples back to the lab. Great reading if you enjoy science history.
https://asm.org/articles/2023/june/hunting-for-antibiotics-i...
Some of the immunosuppressant drugs were discovered from bacteria in soil including Tacrolimus and Sirolimus. And Cyclosporine and Mycophenolate came from a fungus in soil.
I have a kidney transplant and use two of these medications daily.
Easter Island! Both of those.
Tacrolimus was discovered in 1987 by a Japanese team led by pharmacologist Tohru Kino; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.[45] It is produced by a soil bacterium, Streptomyces tsukubensis.[46] The name tacrolimus is derived from "Tsukuba macrolide immunosuppressant".[47]
https://en.m.wikipedia.org/wiki/Tacrolimus
When you study organic synthesis, these kinds of structures are the Holy Grail. Sometimes it takes dozens of steps, and an overall yield of just a few percent to make them synthetically.
There is so much potential in sampling soil. Spinosad was found like this as well only a few decades ago.
> hundreds of complete bacterial genomes never seen before
Welllll that doesn’t sound like a great idea
Just because you don't know they are there doesn't mean they aren't there!
Sounds normal, most bacteria can’t be cultured. Only about 50% of the ones in your mouth can be
There are millions on the lower bound of bacteria species we havn't identified, trillions on the upper bound. Unknown bacteria are literally everywhere, but the simple act of finding and sequencing them is nothing to be afraid of.
Also known as biological dark matter: https://en.m.wikipedia.org/wiki/Biological_dark_matter
Meh, they came from the soil. It's always been here, just never seen by human eyes. That's true of lots and lots of bacteria though - we find new species pretty much every single time we take a stomach sample from someone, let alone random forest soil.
Many bacteria have commensal lifestyles —- scientists don’t feel in control if they can’t culture bacteria in isolation but in nature many bacteria aren’t metabolically complete and son’s live in isolation.