With chemical tweaks, an old antibiotic is now more potent and resistant | Hacker News Reader

With chemical tweaks, an old antibiotic is now more potent and resistant

arstechnica.com

85 pointskposehn34 comments

I think I get the underlying idea, and it is clever.

A traditional antibiotic does one nasty thing to the bacteria. So if bacteria find a single point mutation that helps, there is an evolutionary advantage. This allows resistance to evolve fairly easily once the mutation comes along.

But this is doing several nasty things to bacteria at once, in parallel. So a point mutation that helps with any one attack confers only a minor selection benefit because the others still kill the bacteria. Ideally it would want to evolve a combination of resistances to different attacks in parallel, but that isn't how evolution works.

Resistance can still evolve, but it will be much slower. Improved resistance to whatever is currently the deadliest attack does have a selection benefit, and will spread. But it will be a smaller benefit, and the evolutionary path to full resistance is much longer. So the process is slowed.

I'm a complete layperson to the topic, but wouldn't having more attack avenues that must be evolved against also result in more resources dedicated to survival and eventually compromise the dangerous impact bacteria could have in the first place? i.e. if it's spending energy building anti-anti-bacterial mechanisms, it's not spending as much energy replicating or producing a toxin or whatever.

That's not really how antibiotic resistance develops: it happens at a population-level rather than an individual bacterium level. If, for example, you've got an antibiotic that messes with normal cell wall formation in a particular species, but some in the population randomly have some mutation that still allows the cell wall to function normally, those bacteria will survive the antibiotic. If the infection isn't then controlled by other means, the resistant bacteria will make up a larger percentage of the infecting bacterial population in the next generation. That's why taking full courses of antibiotics is important so that your immune system can focus on the resistant bacteria that the antibiotic can't touch.

You have part of the idea right. However you have to consider that evolutionary pressure works with regards to competition for resources.

So yes a drug-resistant bacteria might be outcompeted for limited resources in a normal environment by bacteria without that adaptation. However, if there is an antibiotic introduced into the environment, the drug-resistant bacteria will probably have proportionally more resources than the non-adapted bacteria did before the drug was introduced, due to a complete elimination of their competition.

This is assuming that the adaptations bacteria have that enables them to be drug resistant harm their fitness in a drug-free environment in the first place. It is entirely possible that the drug was targeting a trait that actually required more resources to produce, but that wasn't selected against because it was basically vestigial.

I think it's a pretty big misconception that the force of natural selection is directed towards absolute efficiency. I'd classify the process of natural selection as a 'good enough' mechanism.

It definitely takes resources for the bacteria to defend against the attack. However not enough to limit its ability to make us sick. (In fact bacteria already have a significant evolutionary incentive to not make us too sick - a dead person doesn't scatter germs as well as a merely uncomfortable person.)

But if you completely remove the antibiotic from the environment, the resources required to maintain the defense offer a small selective disadvantage. Resistant strains of bacteria do not remain resistant indefinitely. Repeated exposure to the antibiotic is needed to maintain resistance. But even very low exposure levels will suffice for that.

It could go either way, but intuitively I think it's much more common that the anti-anti-bacterial mechanisms have negligible costs.

Just like software doesn't usually face sudden new performance issues when vulnerabilities are patched. Sure, openSSL is technically slower once they patched heartbleed, but not much slower. Certainly not enough to be a factor in anyone's decision of whether to use it.

I'm also a complete layperson to the topic, as you may have guessed already.

One interesting thing about the mechanism of Vancomycin is that it doesn't target a protein, it targets a precursor of the cell wall. So a resistance mechanism can't just change the target protein, it has to change the biosynthetic pathway to use a different precursor for the cell wall. And this is how resistance against Vancomycin works, the bacteria start using D-Ala-D-Lac instead of D-Ala-D-Ala, and Vancomycin binds a 1000 times less tightly to that.

One of the changes in this new Vancomycin derivative makes it bind better to D-Ala-D-Lac, neutralizing this particular mechanism for resistance.

What I want to know is: Is there some kind of mode of attack we can use, such that when the bacteria develop a resistance to it, in order to have the resistance they must necessarily become vulnerable to something else.

If you have two or three of these things which are mutually linked. The bacteria can become resistant to one but will become vulnerable to the other.

I am however not a biologist, just a developer, so please excuse me if I am mistaken.

Is such a thing even possible? Is some one working on something like this?

Discover how to do that and you would earn yourself a Nobel in medicine.

There are bacteria that are resistant to every known antibiotic that we have. Certain strains of MSRA and TB are the most scary.

Sounds like a "no free lunch" theorem for molecular evolution.

It seems unlikely you could guarantee that the bacteria could never evolve a way around all the linked attacks, but maybe by making the most obvious solution to one of the attacks be exactly the thing that makes it vulnerable to the other attacks, you could make the hill to climb much steeper.

Extremely clever antibiotic engineering: experimentally determine the most common adaptations that protect against your antibiotic, and incorporate countermeasures to those adaptations in the antibiotic.

How is this different from administering multiple antibiotics at once?

I thought administering multiple antibiotics at once was already common practice to reduce drug resistance.

Two ways.

The first is that this approach made for an antibiotic that can take out bacteria that are resistant to all currently known antibiotics.

The second is that people are inconsistent about mixing antibiotics, so bacteria do encounter opportunities to evolve tolerance one at a time. While this mix of approaches will always be consistently combined.

I get that it's supposed to be "resistant" to drug resistance and all, but nevertheless, it's probably a good idea if we keep this one out of the reach of livestock farmers.

Particularly given that even in their tests bacteria were still (very) slowly gaining resistance.

... and if we only administer it in hospitals (or under medical control anyway): the right quantity for the right time, no more, no less!

livestock farmers have to get a vet to prescribe their antibiotics. Even a few years ago when they didn't they were not allowed to use antibiotics that were useful in humans.

Antibiotic resistance is a real thing, but livestock farmers were not a major concern. Those farmers were consistent and controlled in their use (and couldn't sell anything with detectable levels of antibiotics in it). The real problem was humans who got an antibiotic take it a couple times, felt better and stopped, allowed the bacteria that had a little resistance to survive.

According to this, medically important drugs can still be used for disease prevention in livestock, albeit with the approval of a veterinarian:

https://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnfor...

This seems completely insane to me. I'm not concerned about antibiotics in my food, but rather frequent antibiotic use in animals resulting in resistant diseases which then make the jump to humans.

So what should we do when a cow gets sick of something that an antibiotic can cure? Incinerate it is the only other option I can think of, otherwise you just get more and more cows sick of something easy to treat.

The question of what to do with sick animals is entirely different from the question of preventive antibiotic use. We don't even do that to humans except certain extreme cases like surgery.

Using antibiotics on animals that are actually sick seems OK, as long as it's medically warranted and they take the full regimen (just like humans). Proper antibiotic use shouldn't carry much risk of creating resistance.

First time i recall seeing a link to an article, supposedly about some positive news related to the state of antibiotics. Will we in the closer future start seeing masses of these articles?

kind of like: s/new battery breakthrough/killer antibiotic/g

This is going to kill people

Maybe less than would die from resistant infections initially- but i'm betting the genetic consequences from the side effects will probably kill more people in the long run and weaken the species overall

Does it only work on gram positive? I thought most bad bacteria were gram negative?

gram positive only, but it's still a great idea.

For reference; MRSA, which seems to be typically associated with "superbugs", is gram positive.

Just to clarify, in case anyone isn't aware, MRSA refers to a any number of bacteria in the genus Staphylocaccus which is resistant to methicillin. (Methicillin-resistant Staphylococcus aureus)

It is generally also resistant to another of other common antibiotics such as amoxicillin, penicillin and oxacillin.

The big deal about MRSA is that bacteria can transfer parts of their genome to other bacteria, so if one strain of staph becomes resistant to antibiotics, it can transfer that trait to other strains of staph.

The good news is that all Staphylocaccus bacteria are gram-positive, so you not only gain the ability to treat MRSA, you gain the ability to treat bacteria that might become MRSA.

Somewhat. A few bad Gram positives are coagulase negative Staphylococcus, MRSA, Streptococcus pyogenes/pneumoniae/virdans/mitis etc.

Vanc is often given to immunodeficient cancer patients. Hopefully this will allow more patients to finish their protocols with shorter/fewer delays due to infection.

Can't wait to see the first nanotechnology based antibiotic.

Fascinating development, but Ars's writing is just plain awful. Is there a more academic article on the subject?

There is some more detail here : https://biology.stackexchange.com/questions/60251/how-do-the...

Not an academic article, but Derek Lowe at In the Pipeline has a more technical write-up: http://blogs.sciencemag.org/pipeline/archives/2017/05/30/ant...

Love Derek Lowe! Thank you!

The original paper is on sci-hub and is ten pages long.

Okay, cool. But when do we get genuinely clever and learn to support the body's own defenses instead?

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