Phages vs antibiotic resistant bacteria:Will this solution hold up long term?

Antibiotics don’t work on increasing numbers of pathogenic bacteria. CRISPR modified bacteriophages are proposed as the next generation of antibacterial drugs. Will this work? Heavy use of antibiotics in agriculture and elsewhere gave rise to antibiotic resistance. Won’t transformed phages that are shed by the patients enter the environment and form an evolutionary force driving phage resistance? Assuming that the phages can reproduce themselves in bacteria in the general environment, over time, wont this evolutionary pressure give rise to resistance just like Roundup gives rise to resistant weeds and irresponsible antibiotic use gave rise to MRSA? Maybe even faster than the chemical species that dont reproduce themselves.

One of the big advantages of using phages is that in theory they will also adapt. Bacteriophages adapt rapidly and can perform horizontal gene transfer.

This doesn’t mean resistance will never be a problem, but it may be less likely, or take longer to manifest.

You would have to keep co-evolving the phages in the relevant pathogenic bacterial strains. There exists a large range of different bacteriophage strains - and they each have a very limited range of bacterial strains they prey on, exactly because the two have been co-evolving for the whole history of life on earth. There is no such thing as a broad-band bacteriophage analogous to broad-band antibiotics that work against very wide range of bacteria. The main drawback of phage therapy is that it requires first very careful matching of the correct phage to the pathogen(s) present in the patient, and a comprehensive toolbox of phages adapted to the different pathogens.

One also hopes that we would avoid making the same mistakes we made with antibiotics. Antibiotics work… if used properly. You mostly only get antibiotic resistance from people doing things like stopping the penicillin as soon as their strep throat feels better, instead of finishing the prescription. Or taking antibiotics for a cold, where they can’t possibly do any good.

They’re also extensively misused in livestock, mostly in poultry. Their feed often contains a basically homeopathic dose of tetracycline, to make the chicks grow faster. (This doesn’t work with other animals.) They reach market weight a few days earlier and in mass production, it’s “worth it”, financially anyway.

Some doctors were experimenting with phages in the 1920s and early 1930s, and then the invention of antibiotics made them obsolete - until now.

Kurzgesagt has a segment on this very subject.

An actual experiment that I helped perform in 1955 or so. We took a large flask filled with nutrient fluid and inoculated with E. coli. After a day it had clouded completely and we then added some T-phage (I don’t recall which one, but they feed on E. coli). After a day, the solution cleared and the bottom of the flask was filled with E. coli corpses. But then some mutant strain of the E. coli took over and in another day, the fluid was cloudy again. Then a mutant strain of the phage cleared out the E. coli. We may have let this cycle once more but we had no way of getting rid of all the waste and adding more nutrient that a well-designed experiment would have arranged. It was just a grad student and me (an undergrad lab assistant) doing it for fun. Still it was instructive. So yes, bacteria mutate but so do phage.

If that sort of thing could happen in someone’s body, you’d have recurring bouts of illness and recovery… doesn’t sound fun.

Possibly, but unlike the flask with the mutant E. coli, we do have an immune system.

From what I’ve heard, one of the difficulties of phage therapy is that sometimes the immune system clears out the phages too efficiently.

And that’s why their use so far is investigational only and also only as a last resort.

I was going to post that video because it claims that bacteria can’t become resistant to both phages and antibiotics, that if it gains resistance to one it has to give up resistance to the other.

I have no idea what the logic of that is though.

That’s certainly too strong a statement, since all bacteria have a fair bit of resistance to phages: Any that didn’t would have gone extinct billions of years ago.

But there would still be some truth to it. Every adaptation always has tradeoffs, so it’s more difficult to become resistant to many things than to just one. Sometimes, there might be some specific adaptation that directly increases resistance to one attack while decreasing it to another, but more commonly, you’ll get things like two different adaptations, each of which increases resistance to something, but which both bear a cost (higher energy needs, for instance), and the cumulative cost becomes too much.

Phages mutate, don’t they? (Unless I am mistaken, at a rate higher than bacteria.) The differential of rate based on success would be much greater, I think.

Antibiotics change over vastly different time scales, chiefly bureaucratic.


I got nothing.

But for what definition of ‘works’, as in do we need to withhold antibiotics to a percentage of the population which will result in suffering sickness and death, while perhaps even a ‘elite’ class gets to use them for antibiotics to ‘work’? Or can it work just by people using them when there is a potential medical advantage to using them? Or work if all people followed the exact dosing? Or something else that would have not had antibiotic resistance bacteria develop to the point that they are a threat to us?

The only segment of society you need to withhold them from is the segment who don’t have any bacterial diseases.

It’s not directly linked, resistance is based on many different mechanisms - Resistance to antibiotics involves either mutations in the enzyme/protein that is blocked by the antibiotic, mutations in other enzymes that thereby become capable to degrade the antibiotic or increased production of transport proteins capable of transporting the antibiotic out of the cell. Resistance against bacteriophages might involve mutations in surface proteins that allow the bacteriophage to dock to the bacterial surface in preparation for infection, or improvement of intrinsic systems that protect bacteria against foreign DNA/RNA, such as restriction nucleases. There is also a fast method of adaptation in the CRISPR system: If bacteria are not killed off by a viral infection, they can integrate bits of the viral DNA into their genome to serve as recognition modules for the CRISPR nuclease, which will allow the bacterium to fight off a second infection from the start.

Yeah, I was going to mention how CRISPR and bacterial resistance to viruses were linked:

Interesting that we’re, in a way, using the bacteria’s own defense system against it.

Well- we do not need CRISPR to genetically manipulate viruses - their genomes are usually small enough that you can synthesize them from scratch, and then apply a wide variety of conventional random or site directed mutagenesis methods.

True. I was commenting on its mention in the OP.

Although, now I’m curious if CRISPR methods are more efficient or faster than traditional methods for manipulating viral genomes.

Unfortunately, this article is behind a paywall:

Can CRISPR improve on nature’s own bacteria-killing phages?

This one is open:

Phage Therapy: Turning the Tables on Bacteria

When engineered to incorporate CRISPR components, phages may overwhelm bacterial defenses or transform bacterial functions