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Comment by whatever1 | Hacker News Reader

Given the antibiotic stagnation, could we possibly develop something similar to target bacteria? Aka inject instructions in their genome to self destroy?

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In addition to phage therapy option mentioned here, there's also a class of synthetic polymers that selectively disrupts only bacterial DNA. Those molecules can't cross the nucleus and therefore are not toxic to eucaryotes.

This therapeutic direction has two key advantages over other approaches:

1. There's no way bacteria can develop resistance to it in the next 1b years, since those synthetic polymers bind to free DNA without any preference to particular sequences. Therefore, there's no known mechanism (mutations, horizontal gene transfer, etc) that can provide immunity against this class of agents.

2. Being a "small" molecule it has much less risk of eliciting an immune response ( unlike phages, who may invoke some response from immune cells which can decrease the potency of the treatment)

Here is the latest study i'm familiar with that showed pretty good results in animal models: https://pubmed.ncbi.nlm.nih.gov/33571116/

> and therefore are not toxic to eucaryotes.

Not toxic directly. Disrupting "good" bacteria that we co-exist with isn't always harm free, as I'm sure the people researching those polymers are well aware of.

See: C. difficle infections

That is correct, the same problem exist for current antibiotics which are generally considered safe

Regarding 1, a bacteria could evolve a cell surface that blocks the polymer in the same way a eukaryotic nucleus does.

That is possible, but we're talking about different time constants here. Antibiotic resistance can arise in a few generations. Evolving a different membrane composition that will block that particular toxin and not the other ingredients the cell requires to function (amino acids, carbohydrates, etc), is much less probable to take place in such a short time

Is there a name for this approach?

Bacteria could evolve "antibodies" to these molecules, or enzymes to get rid of them. See CRISPR, plasmid transfer and colony signaling ... bacteria got quite sophisticated defenses.

The whole concept of phage therapy is somehow based on this: Bacteriophages inject DNA into specific bacteria that makes them copy the phage inside them until they burst open.

Basically use viruses against bacteria.

https://www.youtube.com/watch?v=YI3tsmFsrOg

The issue with phage therapy is that it has to be targeted.

With antibiotics, they are very broad spectrum so you can throw augmentin at routine infections and it'll usually work.

With phages, you have to be much more specific. Phage X for bacteria Y. It's not necessarily hard figure out what bacteria it is, but it takes time and expensive lab work.

> It's not necessarily hard figure out what bacteria it is, but it takes time and expensive lab work.

Also you may not have time. If the person has meningitis for example, if you wait to try to figure out what bacteria they have before treating, they will be dead.

Broad spectrum antibiotics are great for this kind of thing in that you can start treatment immediately, and once you figure out the bacteria, narrow the treatment to that type of bacteria.

This is also why bacteria can develop resistance to antibiotics. You can’t develop resistance against something that is 99.999% effective through design

it's not like bacteria haven't developed resistance to phages. what do you think CRISPR is?

Interestingly, in several phage-treated patients, the bacteria then had increased susceptibility to antibiotics. Combination therapy is a remarkable thing.

It is not that bacteria can't become resistant to phages. It is that it is comparatively easy to make new phages to the resistant bacteria. Being viruses, they will evolve with the bacteria they target.

The problem with antibiotic resistance is not the resistance itself, but that we don't seem to find new antibiotics anymore. As a result, once bacteria are resistant to all what we have, it is the end.

But isn't that just a market problem? Once resistance is widespread, won't companies be incentivized to find new antibiotics?

There are presumably a finite number of chemicals that are of the right molecular size to get where they need to go, kill a reasonbly broad range of bacteria, and don't harm humans. We may have found them all already.

We aren’t finding new antibiotics anymore because there are only so many human-safe systemic vulnerabilities to take apart/stop bacteria metabolism biochemically without moving into the genetic arena for further variation. What we are really exhausting are the biochemical differences between our cells and the bacteria cells by wiping out things that make the bacteria unique. This is really bad because it drives additional compatability with the human body while eliminating ways for our immune system to tell them apart as well. We have been driving the evolution of bacteria toward this since we discovered penicillin. What we need is to introduce new genes blocks into wild bacteria that make them susceptible to artificial compounds we create while also conferring a survival and even reproduction advantage to them over bacteria that lack the implanted gene blocks. This would balance out the evolutionary force of the artificial compound vulnerability. I’m fully expecting the Jurassic Park chaos mettling with nature speech but we have precious few options when completely resistant strains of new lethal bacteria inevitably emerge.

That's true, but I have a thesis for why this might be good for the biotech ecosystem.

A lot of people will dismiss phage therapy on economic grounds, suggesting that you'd need to essentially design a new phage therapy for each individual infection you wanted to treat. But, with the advances we're seeing in microfluidics, diagnostics, gene sequencing, computational biology, laboratory automation, and the theory of precision medicine, that host specificity can turn from a disadvantage to an advantage. We know there are a lot of human-dwelling bacteria we wouldn't want to knock but can't save from a broad-spectrum treatment. With a personalized phage therapy, this isn't as much of a concern, and with the above advances, custom therapeutic design can scale economically.

But here's the most important implication of phage-host specificity for biotech business models. When a biotech company gets approved to roll out custom therapies for each individual patient, that opens the door to solving two important roadblocks to biotech innovation. First, firms could get around the problem where they're subject to regulatory scrutiny based on a naive interpretation of the difference between their manufacturing costs and their sale prices. Second, such a paradigm of treatment could permit biotechs to offer gradations of service and charge based on how finely-tuned your therapy is. This would enable them to much more closely fit the demand curve of patients. They could bring the latest technology to the masses cheaply and relatively quickly, while charging a premium for the cutting edge.

Not just this, but our immune system recognizes phages and removes them from the blood stream quickly. So you would need a lot of phages to see some value

The other side of this is that people get long term side effects from drugs like augmentin.

Muscle tightness can lead to injuries, depression, anxiety, etc. Not to mention it takes a very very long time to restore gut flora to pre-treatment conditions.

With enough money I'm sure they could make very very quick tests for each bacteria type that are commonly targeted.

It's not necessarily hard figure out what bacteria it is, but it takes time and expensive lab work.

There are companies out there developing more rapid test panels that will give an answer within minutes or hours, and they charge in the $200 range to test for dozens of pathogens at once.

Someone I know works for such a company, and a lot of the "doctor ran 20 tests for $x000 when they should have just run one" stories in the news are actually about those types of all-in-one rapid tests, and the insurance/hospital doesn't know how to bill it reasonably.

Notably Kaiser Permanente does this

Time is a huge deal. There's a conflict right now between sepsis guidelines and antibiotic stewardship guidelines on when you should start treating, and having to wait for both the diagnostic and the phage prep is sort of a problem.

https://en.wikipedia.org/wiki/Phage_therapy

Even if you could do that, you'd only kill a handful of bacteria. The mRNA platform doesn't contain genetic code to recreate and repackage itself.

Obviously not a biologist, but if you could target a specific protein on the bacterial surface it might work. Alternatively you could CRISPR some human cells that generate the bacteria-killing RNA constantly.

Yes, that would be super cool. But also crazy-risky!! :)

But the risk is not due to chance, its due to the unknowns. Once they're no longer unknowns we'll be able to engineer such a therapy.

Alternatively, once we understand our biology so well, we might as well just patch all the "bugs" so that we don't get infected by harmful pathogens. Or maybe forsake our biology and move on to Silicon ?

Neither do standard antibiotics.

I assume you’re suggesting that phage therapy would require more than a single dose, similar to antibiotic regimens?

Not sure what your point is. If you want to inject genetic material inside an organism to destroy one cell - with the mRNA platform you can only do it once. It won't repackage itself and 'infect' another cell.

If you want to make conditions inhospitable for an organism, you can cause a mass-scale change that affects multiple cells via a drug.

I wonder if that won't work as well given that we're not using this to cure COVID while we are currently sick with it. I don't know if Syphilis booster shots would make sense or if the range of things we could need to be regularly inoculated for would be far too broad for this to be useful.

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