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Comment by btilly | Hacker News Reader

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.

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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.

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.

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.

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.

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