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Old 15th September 2018, 05:24 AM   #1
Captain_Swoop
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Drug-resistant bacteria have a new challenger.

A new molecule can kill deadly strains of common bacteria, such as Escherichia coli and Klebsiella pneumonia, that are resistant to most existing antibiotics. The drug works differently from currently available antibiotics, potentially making it harder for bacteria to develop resistance, researchers report September 12 in Nature.

https://www.sciencenews.org/article/...tant-superbugs

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Old 15th September 2018, 08:39 AM   #2
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Originally Posted by Captain_Swoop View Post
A new molecule can kill deadly strains of common bacteria, such as Escherichia coli and Klebsiella pneumonia, that are resistant to most existing antibiotics. The drug works differently from currently available antibiotics, potentially making it harder for bacteria to develop resistance, researchers report September 12 in Nature.

https://www.sciencenews.org/article/...tant-superbugs
Absolutely an exciting result that is likely to lead to the clinical use of a new class of antibiotics not previously effective agains gram negative bacteria. This will save lives.

But antibiotics are very much "The Red Queen's Race." There will be bacteria that gain resistance to these new drugs. But the idea will be to delay the appearance and spread of these resistant bacteria as long as possible by reserving use of this new class of drugs strictly to the infections that first are treated by, and prove resistant to, the antibiotics in current use.

One of the key problems with developing new drugs to overcome antibiotic resistance is economic. Drug companies don't see any financial incentive to do so. They need to invest a lot of money and screen a lot of possible drugs to maybe find one. And what would the market be for that drug to pay back the investment? Even the current first-level antibiotics such as amoxicillin are typically used just for a few days or weeks and the patient is cured. Unlike the treatment of chronic illness, infections don't create long term sales in the same way Lipitor does. Worse still for a new drug: the new drug will be reserved for those minority of infections that are resistant to the old drug. Expensive to develop and a small market. Many pharmaceutical companies have decided to not bother.

I think that only governments and NGOs will be be sponsoring work in this area. And if they don't fully step up to the plate the future will indeed be horrible. Many of us will die from infections that are currently curable. Even most surgeries will be impossible because post-operative infections are quite common; if not treatable with antibiotics as they are now....
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Old 16th September 2018, 03:55 AM   #3
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Originally Posted by Giordano View Post
But antibiotics are very much "The Red Queen's Race." There will be bacteria that gain resistance to these new drugs. But the idea will be to delay the appearance and spread of these resistant bacteria as long as possible by reserving use of this new class of drugs strictly to the infections that first are treated by, and prove resistant to, the antibiotics in current use.
Is it still considered correct that one of the ways bacteria become resistant is that patients don't finish their whole course? They stop when they feel better, and the remaining bacteria that have survived the initial dosages (not enough population to make the patient feel ill) are more likely to give rise to strains that are more able to resist that particular antibiotic.
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Old 16th September 2018, 04:23 AM   #4
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Originally Posted by smartcooky View Post
Is it still considered correct that one of the ways bacteria become resistant is that patients don't finish their whole course? They stop when they feel better, and the remaining bacteria that have survived the initial dosages (not enough population to make the patient feel ill) are more likely to give rise to strains that are more able to resist that particular antibiotic.
Good real-life experiment to watch

YouTube Video This video is not hosted by the ISF. The ISF can not be held responsible for the suitability or legality of this material. By clicking the link below you agree to view content from an external website.
I AGREE


ETA: It doesn't answer your question as such and I would have liked to have seen what happens with there being a border between wild bacteria and 1000x survivable on one side and the graduation on the other. I'd guess the graduation would win the race to colonise the 1000x agar, which would directly answer your question
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Old 16th September 2018, 12:01 PM   #5
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Thanks jimbob

Interesting, and a bit scary, how quickly that happened.
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Old 16th September 2018, 12:12 PM   #6
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Originally Posted by smartcooky View Post
Thanks jimbob

Interesting, and a bit scary, how quickly that happened.
Yes, I tend to agree with you about youtube videos, but sometimes they are the correct format to present information - particularly trends like that.
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Old 16th September 2018, 12:39 PM   #7
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Originally Posted by smartcooky View Post
Is it still considered correct that one of the ways bacteria become resistant is that patients don't finish their whole course? They stop when they feel better, and the remaining bacteria that have survived the initial dosages (not enough population to make the patient feel ill) are more likely to give rise to strains that are more able to resist that particular antibiotic.
Turns out that's the slow way drug resistance spreads. More often is the widespread use of the antibiotic in the community rather than resistance developing in individuals. (Slow but still important.)

Faster and more important is spread from person to person:

Global spread of three multidrug-resistant lineages of Staphylococcus epidermidis (abstract only)
Quote:
Our study has uncovered the previously unrecognized international spread of a near pan-drug-resistant opportunistic pathogen, identifiable by a rifampicin-resistant phenotype. It is possible that hospital practices, such as antibiotic monotherapy utilizing rifampicin-impregnated medical devices, have driven the evolution of this organism, once trivialized as a contaminant, towards potentially incurable infections.
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Old 16th September 2018, 12:49 PM   #8
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Eventually after distracting them with phage therapy and this thing if it ever works, we could potentially go back to penicillin and steptomycin, sulfa drugs we've stashed away for decades.
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Old 16th September 2018, 12:51 PM   #9
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Originally Posted by Venom View Post
Eventually after distracting them with phage therapy and this thing if it ever works, we could potentially go back to penicillin and steptomycin, sulfa drugs we've stashed away for decades.
I like the idea of phage therapy, and I guess predatory bacteria as well. Those will co-evolve with their prey and should be pretty targeted.
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link is 2015 data (2013 Data below):
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US 16.4% of GDP of which 48.2% is public expenditure - 7.9% of GDP is public spending
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Old 16th September 2018, 03:35 PM   #10
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Originally Posted by smartcooky View Post
Is it still considered correct that one of the ways bacteria become resistant is that patients don't finish their whole course? They stop when they feel better, and the remaining bacteria that have survived the initial dosages (not enough population to make the patient feel ill) are more likely to give rise to strains that are more able to resist that particular antibiotic.
I'm sort of late for an answer - but that is an interesting question. The conventional wisdom has been as you said, that failing to complete the whole course leads to resistance. But some recent studies have suggested that a shorter course of antibiotics than is now typical may still be sufficient to cure most infections and actually reduces the chances of a resistant strain emerging because the bacteria are exposed for less time and therefore have less time to be selected for resistance.

Another interesting, relatively recent observation is that often within a population of drug-sensitive bacteria there are rare "persister" bacteria that are resistant to multiple antibiotics not because of mutations but because of their particular physiological state at the time. They are relatively dormant and metabolically inactive. So they survive the drug treatment even though the bulk of their genetically identical siblings die. Later they can begin to proliferate and generate the mutations that can confer a more permanent form of resistance.

Interestingly the same idea probably applies to many cancers.
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Old 16th September 2018, 03:47 PM   #11
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Originally Posted by jimbob View Post
I like the idea of phage therapy, and I guess predatory bacteria as well. Those will co-evolve with their prey and should be pretty targeted.
As with any host and prey they are likely to set up an equilibrium - an ecosystem just like wolves and elks. When the predators kill a lot of prey, the prey population drops, the predators starve (or, if a phage, can't find a new host), and the predator population drops. Then the prey population can increase... Repeat until a stable equilibrium is reached. Or see-saw over multiple years.

It is rare for the prey population to ever reach zero. There are still rabbits in Australia despite the introduction of myxomatous virus to kill them. It helped: there are fewer rabbits than before the disease, but resistance is slowly growing.

But I bet there are strategies that might help in the clinical use of phage in terms of application and time courses. Plus if the phage reduce the bacteria to a small enough population the immune system should be able to zero out the remaining ones.
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Old 16th September 2018, 04:44 PM   #12
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Originally Posted by Giordano View Post
One of the key problems with developing new drugs to overcome antibiotic resistance is economic. Drug companies don't see any financial incentive to do so. They need to invest a lot of money and screen a lot of possible drugs to maybe find one. And what would the market be for that drug to pay back the investment? Even the current first-level antibiotics such as amoxicillin are typically used just for a few days or weeks and the patient is cured. Unlike the treatment of chronic illness, infections don't create long term sales in the same way Lipitor does. Worse still for a new drug: the new drug will be reserved for those minority of infections that are resistant to the old drug. Expensive to develop and a small market. Many pharmaceutical companies have decided to not bother.

All of that would go away if it was tax payer funded & public. (I realize you go into that in the next paragraph. I just wanted to make it clear.)

No civilized government should make it legal for companies to own drugs.
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Old 16th September 2018, 06:20 PM   #13
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does anyone think penicillin and sulfa drugs will work once again after today's most dangerous pathogens have not tasted them for almost a century?
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Old 16th September 2018, 07:47 PM   #14
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Originally Posted by Venom View Post
does anyone think penicillin and sulfa drugs will work once again after today's most dangerous pathogens have not tasted them for almost a century?
Depends HOW the resistance is accomplished. If resistance is achieved by merely changing some structural molecules around a bit to alternatives that have comparable efficacy and metabolic cost then there's little or no pressure back toward a non-resistant state. If the pathogen is synthesizing some entirely new or extra compound...or variants of existing metabolites that are less effective / more costly...then non-resistant strains will outcompete resistant ones in the absence of continued selective pressure towards resistance.
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Old 16th September 2018, 09:16 PM   #15
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Cool.
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Old 16th September 2018, 10:15 PM   #16
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Originally Posted by Venom View Post
does anyone think penicillin and sulfa drugs will work once again after today's most dangerous pathogens have not tasted them for almost a century?
First off, both those drugs are still in use.

Second, once drug resistant genes are out there, they don't go back. Shortly after you put selection pressure on an organism, generally the resistance will show up again. We see this with HIV drugs. There is some benefit but it is short lived.

Here's a fun fact. If you expose certain bacteria to a toxin (antibiotic or other) they shut down their DNA repair mechanism thus increasing mutations. Mutations are how rapidly reproducing organism develop resistance.
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Old 16th September 2018, 11:27 PM   #17
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Originally Posted by Giordano View Post
As with any host and prey they are likely to set up an equilibrium - an ecosystem just like wolves and elks. When the predators kill a lot of prey, the prey population drops, the predators starve (or, if a phage, can't find a new host), and the predator population drops. Then the prey population can increase... Repeat until a stable equilibrium is reached. Or see-saw over multiple years.
I suspect that depends on the size of the environment. Introduce wolves to a small island with some deer on it and they very well might kill off all the deer before their population falls due to starvation. If it's a large enough island chances are some of the deer will avoid predation until the wolves numbers start to fall.

Of course this is just speculation on my part.
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Old Yesterday, 04:40 AM   #18
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covalent modification of the target enzyme

I just skimmed the article in Nature (doi: 10.1038/s41586-018-0483-6.). This drug has a nitrile group that forms a covalent bond with a catalytic lysine residue on the target enzyme, not the catalytic serine residue, as one might have expected. Molecules that work by forming a covalent bond used to be thought to be poor candidates for development into drugs, but that thinking has changed in recent years, from what I have read (Singh, J., Petter, R. C., Baillie, T. A. & Whitty, A. The resurgence of covalent drugs. Nat. Rev. Drug Discov. 2011).
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Old Yesterday, 07:09 PM   #19
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Originally Posted by Chris_Halkides View Post
I just skimmed the article in Nature (doi: 10.1038/s41586-018-0483-6.). This drug has a nitrile group that forms a covalent bond with a catalytic lysine residue on the target enzyme, not the catalytic serine residue, as one might have expected.
Right! Yes, exactly. I thought so myself.
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Old Today, 04:27 AM   #20
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serine proteases and serine esterases

Serine proteases (a large and diverse family of enzymes) and serine esterases form a temporary covalent bond between the critical serine residue and the substrate; in other words serine is a nucleophile. Therefore targeting this catalytic residue makes sense. Penicillin-type antibacterials form an essentially permanent covalent bond with a serine residue within the enzyme transpeptidase (IIRC this enzyme is known by several names). Acetylcholinesterase is a serine esterase that is a target of nerve agents. The normal role of a histidine residue (or in this case) a lysine residue is to be a general base that removes the proton from serine, making the serine a better nucleophile.

On page 190 of the Nature article they specifically mention that they were aiming for the catalytic serine residue, but it seems as if the compound reacted with the nearby essential lysine residue. Nothing wrong with that if it works, but it is one example of how hard it can be to design drugs.
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Old Today, 08:20 AM   #21
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Originally Posted by Chris_Halkides View Post
Serine proteases (a large and diverse family of enzymes) and serine esterases form a temporary covalent bond between the critical serine residue and the substrate; in other words serine is a nucleophile. Therefore targeting this catalytic residue makes sense. Penicillin-type antibacterials form an essentially permanent covalent bond with a serine residue within the enzyme transpeptidase (IIRC this enzyme is known by several names). Acetylcholinesterase is a serine esterase that is a target of nerve agents. The normal role of a histidine residue (or in this case) a lysine residue is to be a general base that removes the proton from serine, making the serine a better nucleophile.

On page 190 of the Nature article they specifically mention that they were aiming for the catalytic serine residue, but it seems as if the compound reacted with the nearby essential lysine residue. Nothing wrong with that if it works, but it is one example of how hard it can be to design drugs.
I remembered (if vaguely) the Ser/His/Asp triad in most serine proteases from college, but I hadn't know about the variations on this until I just looked it up. The Ser/Lys catalytic dyad in the signal protease is particularly interesting. Thanks!
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Old Today, 08:45 AM   #22
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Yes indeed.
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Old Today, 08:48 AM   #23
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Originally Posted by Captain_Swoop View Post
A new molecule can kill deadly strains of common bacteria, such as Escherichia coli and Klebsiella pneumonia, that are resistant to most existing antibiotics. The drug works differently from currently available antibiotics, potentially making it harder for bacteria to develop resistance, researchers report September 12 in Nature.

https://www.sciencenews.org/article/...tant-superbugs
Yeah, don't **** with homo sapiens.
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Old Today, 08:57 AM   #24
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Originally Posted by arthwollipot View Post
Right! Yes, exactly. I thought so myself.
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