Whenever I hear "antibiotic that doesn't evoke bacterial resistance" I think, "You just haven't looked hard enough yet. The bacteria will 'find' a way."
If that premise is true then it should imply two things:
1. If we have "enough" "orthogonal" treatment options, we should be able to rotate on long enough time scales to avoid resistance to all treatments. Like cicadas with their prime numbered long sleep cycles.
2. Maybe we can find a treatment whose resistance is so difficult that it makes the newly resistant bacteria too vulnerable to other threats to survive in the wild, or at least at a serious disadvantage against non-resistant variants.
Are these completely off base?
But if small exceptions (because you know some rich person is going to get sick and hire a rogue lab to make something that's supposed to be paused) wouldn't ruin the whole scheme then it seems feasible.
If you do not actually have enough antibiotics to cycle through, then yeah, it would not really work.
So, yes you have the right idea. There is a general push to not do outpatient procedures in hospitals for this very reason.
This is something that has crossed my mind in the past. We rotate antibiotics in a logical fashion, in a manner similar to the way we rotate crops.
But as someone else responded more eloquently, you're gonna have a hard time telling grandma's family that the most effective antibiotic is currently "out of rotation." And honestly, I'd be pretty upset if it were my grandma, too.
This seems likely, to the point where I took it for granted. The fact that you know that you're in an arms race does not mean that you should stop developing new arms? Maybe the opposite. Even if the advantage gained is temporary.
Certainly not implying it's impossible, the rate at which bacteria reproduce gives ample opportunity for mutational evolution, so relative to more complex organisms they are well positioned to develop immunities to novel synthetics. But it isn't necessarily guaranteed that the mechanism exists for it to happen.
I agree. Never say "never."
But a lot of the time, resistance is simply a matter of tinkering with target of the antibiotic (add a methyl group here and, voila! the antibiotic no longer binds effectively).
Then there are multi-drug efflux pumps (https://en.wikipedia.org/wiki/Efflux_(microbiology)) that "indiscriminately" toss shit out of the bacterial cell.
A pharmacist relative who works with hospitals told me of a case where they detected excess infections, traced it to a particular operating room, then got stuck for some time before they found the source — a colony of resistant bacteria living on the spout of the antibiotic soap dispenser used by the operating team to wash hands pre-op. Another item added to the checklist.
These concerns are addressed at least to some extent in the paper.
Note also, the title not necessarily means "resistance impossible", it may mean "currently no resistance, even after explicit attempts to evoke it, using methods that for other antibiotics do result in resistance".
I myself am not competent to judge. You may be right in your skepticism.
From the paper:
> The evolution of bacterial resistance to COE2-2hexyl was analysed in S. Typhimurium and MRSA, using either serial dilution or morbidostat-based experimental evolution (see Methods). Serial dilution. No high-level COER mutants (≥50 × MIC) of either S. Typhimurium 14028 or CA-MRSA USA300 were isolated after serial dilution for 21 days; however, low-level COER mutants were recovered in both organisms (8 × MIC and 4 × MIC, respectively) (Supplementary Fig S1a; Supplementary Table S4a and b). Morbidostat. Although high-level CIPR mutants of wild-type E. coli (BW25113) were obtained after morbidostat culture for >3 days (64-128 × MIC),35 no COER mutants were observed under these conditions. Therefore, E. coli mutL (JW4128) and wild-type A. baumannii ATCC 17978 were assessed for COER mutants since both strains possess an inherently higher frequency of mutation (∼10-100-fold), resulting from deficiencies in either methyl-directed mismatch repair or the intrinsic DNA damage-inducible response, respectively.45,46 Only low-level COER mutants (2-4 × MIC) were recovered from either of these hypermutable strains, which is in marked contrast with the high-level CIPR mutants (128 × MIC) observed for A. baumannii35 (Supplementary Fig. S1b; Supplementary Table S4c–e). Whole genome sequencing of COER mutants revealed mutation(s) in genes encoding essential functions involved in membrane remodelling and secretion (Supplementary Table S4a–e). Examples include: Gram-negative secA and bamA involved in outer membrane protein biogenesis and lptD from the lipopolysaccharide translocation complex47,48; pgsA from the phosphatidylglycerol biogenesis pathway49; and Gram-positive pmtR from the cytolytic peptide toxin transporter pathway.50 Consistent with this observation, a de novo constructed S. Typhimurium secA nonsense mutant (G880∗ (GGA→TGA))—derived from COER mutant analysis from serial-dilution—showed a two-fold increase in COE resistance (Supplementary Table S4a). Taken together, these data suggest that COE2-2hexyl did not evoke significant bacterial resistance, potentially due to specific effects on essential functions involved in membrane remodelling and secretion.
[... they go on in the Discussion section ...]
BTW, the "serial dilution" method name sounds to me like what is illustrated by this famous video: https://www.youtube.com/watch?v=plVk4NVIUh8
After their complete u-turns on COVID origin theory and hydroxy chloroquine, I would seriously reconsider your statement.
https://www.theguardian.com/world/2020/jun/10/surgisphere-sa...
edit: more dramatic...
The Lancet has made one of the biggest retractions in modern history. How could this happen?
https://www.theguardian.com/commentisfree/2020/jun/05/lancet...
But here's one thing to keep in mind with respect to this specific research. They examined the ability of two specific strains of bacteria to develop resistance. There are tons of microbial pathogens mixed together and 'promiscuously' swapping genetic material [including those for resistance] out there in the real world. Two specific strains (one for S. typhimurium and one for S. aureus) in isolation are like two water molecules in the ocean. It's a nice start, but it's far from the finish line.
Also, keep in mind that the corresponding authors are academics (UCSB). The bar is pretty low with respect to what they have to deliver. I don't mean that as an insult--their job is basic research. Their job is not to make a marketed product.
I used to be an "ivory tower snob." I thought university profs were a cut above industry researchers, but it's far more mixed (in my experience) and the research (between industry and academia) is judged by different metrics. In biotech, your research needs to lead to something that actually makes money. Otherwise, nobody cares. Academic research is far more exploratory, which is what I think this paper is an example of.
Great video, ( if it's not fictitious)
Yes. It's difficult to acquire resistance to heat and alcohol. The problem is that heat and alcohol are indiscriminate in their ability to kill cells, including yours and mine.