Revolutionary Dual Action Antibiotic Makes Bacterial Resistance Nearly Impossible (scitechdaily.com) 54
A new type of antibiotic "targets bacteria in two ways," writes SciTechDaily, which "could make it 100 million times harder for bacteria to develop resistance, according to recent research from the University of Illinois Chicago."
Their experiments demonstrate that [a class of synthetic drugs called] macrolones can work two different ways — either by interfering with protein production or corrupting DNA structure. Because bacteria would need to implement defenses to both attacks simultaneously, the researchers calculated that drug resistance is nearly impossible. "The beauty of this antibiotic is that it kills through two different targets in bacteria," said Alexander Mankin, distinguished professor of pharmaceutical sciences at UIC. "If the antibiotic hits both targets at the same concentration, then the bacteria lose their ability to become resistant via the acquisition of random mutations in any of the two targets."
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.... "The main outcome from all of this work is the understanding of how we need to go forward," Mankin said. "And the understanding that we're giving to chemists is that you need to optimize these macrolones to hit both targets."
Thanks to long-time Slashdot reader schwit1 for sharing the news.
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.... "The main outcome from all of this work is the understanding of how we need to go forward," Mankin said. "And the understanding that we're giving to chemists is that you need to optimize these macrolones to hit both targets."
Thanks to long-time Slashdot reader schwit1 for sharing the news.
next year (Score:2)
"we've detected a new type of bacteria that is immune to everything we can throw at it, including nuclear warheads. Humans are doomed"
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Admittedly I know little about the topic, but it doesn't sound like it will come to that:
Macrolides, such as erythromycin, block the ribosome, the protein manufacturing factories of the cell.
It sounds like whether you treat the patient with it or not, the outcome will be the same.
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The tricky part was getting into the Andaman Islander population. That turned out to be way harder than developing the thing in the first place. But it's all done now.
The obligatory (Score:5, Insightful)
Someone else finish it.
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I was going to go with DDT.
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Life, uh,
Don't talk to me about life!
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Life, uh,
... but resistance is futile.
lets face it. as a nerd, it's really hard to take a stand on this.
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"If there's one thing the history of evolution has taught us, it's that life will not be contained. Life breaks free, it expands to new territories and crashes through barriers, painfully, maybe even dangerously, but, uh... well, there it is. Life, uh, finds a way."
And how is this different (Score:3, Insightful)
From just giving two different antibiotics at the same time? The patents expired on them and there's a new patent on this one?
Re:And how is this different (Score:4, Funny)
Oh, everything's stolen nowadays. Why, the fax machine is nothing but a waffle iron with a phone attached.
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It seems to me low levels of multiple existing antibiotics could work by slowing down the metabolism of bacteria enough for the body's immune system to keep up. Most antibiotic work-arounds involve extra metabolic steps a microbe has to take. If multiple antibiotics make it have to take too many total steps, then it reproduces too slow to outpace a regular immune response.
Re:And how is this different (Score:5, Informative)
The different antibiotics might not reach the same spots in the same concentrations at the same time (different pharmacokinetics); the different effects might even be fully serial in some spots. This combination ensures that both mechanisms are always equally active in every spot, further reducing the risk of the development of resistance.
Re:And how is this different (Score:5, Interesting)
Though fighting resistance is an important goal, efficacy is the most important criteria when deciding if a drug program is going to be used. While combining macrolides with fluoroquinolones can be effective, studies have indicated that fluoroquinolones alone are often more effective than combination therapies for certain conditions, such as pneumonia. -- So even though using these drugs in conjunction might reduce resistance, they are not used together because efficacy is more important and doctors don't give a second drug to a patient than is unlikely to have a positive effect for that patient.
Other studies have shown that at least 3 effective drugs attacking 3 different mechanisms is the best approach to fighting resistance.
If Macrolones are not more effective than just one of these drugs, then they are unlikely to become widely used despite other benefits. Larger molecules are rarely more effective than smaller molecules with the same binding sites, so they face an uphill battle in this regard. Because it is just one drug, it does have a better chance of being used that two separate drugs. If a Macrolone is found to be 99% as effective as a fluoroquinolone against pneumonia I could see it coming into widespread use for that case. But if it's numbers look more like 80%, it will not get used.
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Do you know if the combo molecule can still wreck ligaments or does the different shape prevent that?
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For the life of me I can't tell if I just read something impressively informative, or if it's the start of the latest Dr Seuss book.
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You could always try reading the article. They explain the difference.
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The new antibiotic will cost enough to make you get a second or third mortgage. The two drug combo is practically worthless, all it can do is cure the patient.
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It might even be worse than certain combination therapies, as I explain in my other comment below.
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It is ONE antibiotic with TWO mechanisms.
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They do actualy do this. The problem is when the drugs are deployed singularly elsewhere it still gives bacteria an ability to individually adapt to the mechanisms.
By comparison the three drug combo for HIV (yes I know antiviral, but its the same principle re resistance) is almost *always* given together, and thats why HIV despite being a rampant mutator has been unable to adapt itself to defeating it (although HIV's diabolical ability to insinuate itself into the patients genome has proven very tough to er
Plasmids (Score:3)
One strain develops immunity to one of the targets and the other strain the other. Floating plasmids for each mutation come together in one lucky organism and they are then immune to both. There will be areas or situation where the antibiotic is weak such that evolving one at a time is still helpful to some bacteria; they then combine forces like superheros via plasmids.
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100,000,000 = 10^8
The number of microorganisms inhabiting the GI tract has been estimated to exceed 10^14, which encompasses 10 times more bacterial cells than the number of human cells and over 100 times the amount of genomic content (microbiome) as the human genome
Based on 10^14 bacteria ,100,000,00 times harder doesn't seem like that great a buffer.
However making it harder is definitely better. There is obviously a lot of value in making it take a lot longer for bacteria to develop resistance.
Re: Plasmids (Score:1)
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My reasoning didn't assume frequent mutation successes.
Re:Plasmids (Score:5, Interesting)
Well, that can't happen if it's a single agent that does both because any individual with a single protective mutation would still be dead (or more specifically wouldn't have a reproductive advantage) and thus the mutation wouldn't propagate. Although this would only apply if this agent was entirely novel. If it happens to be one molecule that has the same effect as two separate existing drugs that are already used separately. From this article i take it the new class are "similar to" (but adequately distinct from) the two other classes mentioned.
That said, according to this random 2014 paper, at least then it was generally not recommended to try to achieve this effect currently (or as of ~15 years ago) by combining compounds.
Definitive combination therapy including two antibiotics to which the bacteria are susceptible has been suggested to improve clinical outcome as compared with monotherapy for critically ill or neutropenic patients and severe infections with Pseudomonas spp. (11,12). Further, it has been argued that combinations should be used to prevent emergence of resistance during therapy (13). However, recent meta-analyses conclude that the existing clinical evidence is insufficient to support the use of definitive combination therapy for these reasons and that combination therapy is associated with an increased risk for ototoxicity, nephrotoxicity, bacterial superinfections, and selection of resistant strains (3,5). It has therefore been recommended to de-escalate antibiotic treatment to the most appropriate single agent as soon as the antibiotic susceptibility profile of the causative pathogen is known (5,10). ...
https://www.ncbi.nlm.nih.gov/p... [nih.gov]
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Hang on a minute... (Score:2)
One strain develops immunity to one of the targets and the other strain the other. Floating plasmids...
Apropos of nothing, if a strain develops immunity to one of the targets, won't it be killed off by the 2nd target?
I'm sure your reasoning is logical, I'm just not sure which type of logic you're using.
Care to elaborate?
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The reasoning is that when a bacteria dies, its DNA is strewn out .. other nearby bacteria take up pieces of its DNA and make whatever its DNA specifies and if it confers an advantage it spreads. The slight flaw in the logic is that only one out of a few trillion bacteria will have the resistance mutation, so the chance that its DNA is read by a bacteria that happens to be resistant to the second target is low UNLESS being resistant to a target somehow enabled the bacteria to live slightly longer (outlive m
Meh ... (Score:5, Insightful)
A new type of antibiotic "targets bacteria in two ways," writes SciTechDaily, which "could make it 100 million times harder for bacteria to develop resistanc ...
My money is still on the bacteria.
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Or the Grey Goo...
Look on the bright side . . . (Score:2)
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My money is still on the bacteria.
Mine's not. Despite us fucking up antibiotics and their application in amazing ways they've still not successfully hit us with a superbug in the level of a viral pandemic and that's despite decades of using the same anti-biotics. If it were 100 million times harder to develop a resistance we would be pretty safe.
False (Score:5, Informative)
100 million is nothing for bacteria, there are a zillions of bacteria .. but let's leave that aside. The premise of this, which is basically combination therapy (giving 2 or 3 drugs at the same time), is that the bacteria will succumb to B if it doesn't succumb to A. Unfortunately, nature doesn't work like that. Having been and still involved in therapeutic design .. the issue is that RESISTANCE occurs a number of ways -- too numerous to list here. One is efflux pumping. Efflux pumps are molecules that a cell, such as bacteria, produces to expel a target. The bigger your molecule is, the more likely an efflux pump mutation will develop that can attach to it and deport it from the cell. With macrolones, which are similar to macrolide drugs such as erythromycin, we'd likely see the same problem.
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Yeah, we've heard this song before (Score:4, Interesting)
Several decades ago, it was thought that insects couldn't develop resistance to a particular strain of the natural insecticide Bacillus thuringiensis (I don't remember which) for similar reasons. Well, some commercial growers started over-using the stuff and of course the "impossible" happened.
https://experts.arizona.edu/en... [arizona.edu]
Nifty, sounds great (Score:4, Funny)
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Walgreen's? I want it at McDonalds next to the ketchup.
Like the unsinkable Titanic (Score:3)
We'll see. :-)
Nearly? (Score:4, Insightful)
The problem is always with the 0.000001%. If the start multiplying...
weird (Score:1)
These stories always bring out the bacteria worshipers.
Seriously, there are some people who root for the bacteria. It's very strange ...
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He he. and it's like religion, so.. you should be too.
I'll try to convert you.
How about considering a balance between clean and dirty.
So I would say some simple things like handwashing are really quite a good thing, but you don't necessarily want the the anti bacterial all the time... So then with antibiotics, you can cause problems in your guts by killing off some of the good guys. So don't over do it.. sometimes I think you would just take the anti biotics if
That word does not meant what you think it means.. (Score:2)
Hold my beer
Not quite as hard to evolve resistance (Score:3)
If this new drug(s) are targeting two aspects of bacteria that have been individually targeted by existing drugs then a bacteria that already has resistance to one of these would only need to develop resistance to the other. Not nearly as unlikely as if virgin bacteria were to develop resistance.
Jeff Goldblum has entered the chat (Score:2)
As he once famously said:
"Life finds a way."
So goodbye to your gut flora (Score:2)
...and hello to the necessary ingestion of poop pills or sprays to get your digestive system back up and running.
It's a brave new world.
Like software bugs that can't be exploited (Score:2)
In much the same way as a software vulnerability that relies on a 1-in-a-million race to work, "nearly impossible" is irrelevant. The software problem is that attacking programs can just keep trying a few million times; the biological version has billions of bacteria, each a chance to find a way to become resistant. They've evolved to be very good at this.
Hold my beer ... (Score:2)
Inject it into 30 billion chickens and have the residue go into surface water and lets see how long impossible lasts.
Energy cost of resistance and variety of defenses matters too ... we're not very good at variety, we can't even get over our greed to let animal agriculture use antibiotics as prophylactics.
PS. the US under Biden is currently trying to block the EU laws which forbid prophylactic use of antimicrobials for imported meat.
https://tradeconcerns.wto.org/... [wto.org]
Does the patient survive this antibiotic? (Score:2)
There are always at least two facets that determine whether an antibiotic can be used:
1. Does it kill bacteria?
2. Does the patient survive it?
So how does this one score on the second one? An antibiotic which also kills the patient isn't really useful.
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They will ruin it by using it everyday on cows (Score:2)