My understanding is that in this case bacteria would have to develop resistance to two mechanisms at the same time, which is much more difficult.
Mandatory quote: "Life, uh, finds a way"
Hitting the population with multiple mechanisms simultaneously masks the selective advantage of slightly better phenotypes against the individual attacks.
There's a spread in individual characteristics, and if the attacks are applied independently, the more vulnerable individuals perish more readily and the genetic distribution goes on to trying states mainly near the more resilient ones against that attack. But faring a bit better against Attack-1 is practically no better than not, if Attack-2 is always going to wipe out all Attack-1-resistance phenotypes about equally anyway.
Executed just right it attacks the conditions for gradual evolution by breaking most of the corrective signal.
From the article, it does look like they're smushing two antibiotic active sites into one molecule, so it seems a somewhat similar idea
> 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)?
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.
In the normal dual antibacterial cases just developing a single resistance and acquiring the right plasmid is enough.
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
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.
There's always the possibility of a microbe/prion/other that can attack and consume all DNA based life forms. Or a 'nearby' gamma ray burst that sterilises everything within 200 light years.