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Isn't it exactly the same situation? In one case you have two substances that attack cells by two different mechanisms, and in the other you have a single substance that attacks cells by two different mechanisms. In either case a strain that doesn't have resistance to both mechanisms will get wiped out, since just one of them destroys the cells or prevents them from reproducing. Even if some sub-strains develop resistance to one of the mechanisms, it won't matter because they will get wiped out by the other.

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But if doctors don’t always prescribe these two antibiotics to be used in tandem, then microbes will have an opportunity to evolve resistance to each one in isolation, putting those resistant genes out in the world. Whereas in this case, any bacteria ever encountering this drug will be hit by both mechanisms at once.

... but the article describes that the antibiotics being discussed combine structures from classes of antibiotics which are already used independently.

> Macrolones are synthetic antibiotics that combine the structures of two widely used antibiotics with different mechanisms. Macrolides, such as erythromycin, block the ribosome, the protein manufacturing factories of the cell. Fluoroquinolones, such as ciprofloxacin, target a bacteria-specific enzyme called DNA gyrase.

So if macrolides and fluoroquinolones are each used independently already, and strains resistant to each of them independently, and these strains have an opportunity to co-occur and do horizontal transfer, wouldn't we expect that to have resistance to a single drug that combines both mechanisms? I guess, when a strain develops resistance, is it to the mechanism overall (e.g. a more robust ribosome or differently shaped DNA gyrase enzyme) or is the resistance somehow specific to a specific molecule (e.g. some enzyme that finds and breaks-down the drug based on other aspects of its structure)?

Good observations. There are many possible mechanisms for resistance, and with this involving bacteria I expect pretty much all are sooner or later used. Some ways are more specific to the substance, such as changing the target to fit worse or be less sensitive to the effect. Some can be quite general, such as actively pumping the molecules out of the cell.

In these cases there won't probably won't be that much wiggle room for altering the targets. Ribosomes and DNA-associated enzymes tend to be very very busy doing critical work against a lot of substrates and products, and are already heavily optimized for their normal tasks. I'd say it's no coincidence these mechanisms were chosen for a novel antibiotic attempting to mitigate resistance development.

Degrading the antibiotic, throwing it out, etc are still viable options, but it's still very nice to see someone finally trying to do this more right, even if basing it on elements of existing classes adds some risk that there are strong initialization states for resistance development out there.

Good question. Take many many antibacterial molecules to kill a bacteria, so there are two plausible methods. The first is that two compounds can have different pharmacokinetics. That is to say, they move through the body in different ways and have different concentration profiles.

The second is about how they are used. Two separate compounds with the same pharmacokinetics could be effective if you use them in parallel, but you have to contend with the fact that real human users may not always use them that way. If two different companies make compound a and compound B, it is virtually impossible to prevent someone somewhere from using them separately

I meant that if you have two separate substances, we can reasonably assume they will also be used individually, giving bacteria chance to develop resistance. Then strains with different resistances meet in one organism and swap genes.

Although that's extremely simplified. I recall reading that the usual mechanism is somewhat different. When you take one antibiotic to fight one pathogen, also attacks other bacteria in your gut microbiome (also those benign and even useful). Those bacterial also develop resistance. Unfortunately they can later share their resistance genes with harmful bacteria.

Okay, but unless the older single action antibiotics are completely taken out of the market, it doesn't really matter, does it?

I'm not a biologist, but I'm guessing that having the concentrations of two antibiotics peak at the same time etc is much much trickier than having one molecule with two mechanisms of effect. Thus in actual (not perfect) use you end up with both effects active within a bacterium at one time, rather than potentially having some distance between the peaks.

From the article, it does look like they're smushing two antibiotic active sites into one molecule, so it seems a somewhat similar idea

The antibacterial resistance is often on small DNA loops called plasmids which are often and easily exchanged between bacterial species. I assume this has to do with that, either the resistance would have to develop twice in the main genome or twice on the same plasmid.

In the normal dual antibacterial cases just developing a single resistance and acquiring the right plasmid is enough.

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