[mordymoop]

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.

[abeppu]

... 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)?

[etiam]

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.