6 ms·

I think the real meat of this article is here: "...strikes multiple targets, including cell walls...Since the lipid structures it attacks don’t evolve as quick

I think the real meat of this article is here: "...strikes multiple targets, including cell walls...Since the lipid structures it attacks don’t evolve as quickly as frequently mutating proteins, it may take the bacteria longer than usual to develop a survival tactic." Proteins change often and quickly, but basic cell structures may take longer or never adapt. But I'm not a pathobiologist, I just play one on the Internet

hga 12y ago
So do the β-Lactam antibiotics (e.g. penicillin), but that doesn't stop a host of unrelated resistance mechanisms: enzymes that directly attack it, mutations to the protein(s) that are necessary for entry into the bacteria, and probably the pumps that actively remove various antibiotics. Given that this was discovered from existing bacteria, there's a significant chance nature has already done the first and last of those. The middle mechanism is likely possible for any bacteria, if you have enough to start with (there's nothing I could find with Google in a minute to describe teixobactin's transport mechanism). In general there was a rule of thumb when I was doing microbiology of this exact nature (an antibiotic created by some strains of E. Coli), if you exposed a million bacteria cells to a generic antibiotic, 1 would would survive due to a mutation (a useful number in microbiology, likely dead meat in the body). Streptomycin was more effective, 1 in a billion. ADDED: it's implied by the Nature abstract that the researchers have tried this general approach, that they were not able to find spontaneous resistance mutations in a couple of the standard nasties. But extending on the above thesis, ecologically, there's a respectable chance some bacteria out there have developed defenses. It's a jungle out there, and e.g. in your gut, that's why fungi and bacteria developed antibiotics in the first place. They aren't expending resources just to allow us to kill the inconvenient ones.
- pcrh 12y ago
  From the Nature article, the claim that resistance to teixobactin is hard is based on an attempt by the authors to induce resistance by culturing S. aureus or M. tuberculosis in the presence of sub-lethal concentrations of teixobactin for 27 days and seeing if resistant clones evolved. They did not observe any. That doesn't mean it's impossible, though. Plasmids for example are a source of resistance that doesn't require mutations. Edit: deleted incorrect information about b-lactamase.
  - Fomite 12y ago
    No. Beta-lactams inhibit cell wall synthesis by binding with penicillin binding proteins and preventing their function. Beta-lactamase is a resistance mechanism against this family of drugs.
    - pcrh 12y ago
      You're correct, I'll correct my post.
  - hga 12y ago
    [ Deleted β-Lactam stuff. ] Nature asked me for $$$ to read the article, so ... from your description, that's leaving out the hard, fast test of just culturing several billion of those, adding a lethal concentration and seeing if there are any survivors. Which is how I gather one found spontaneous transport mutations, at least circa 1977. The state of the art has likely improved, and these guys used novel microbiological methods to find the bacteria that produce teixobactin in the first place. ADDED: thanks to betatim's link to the full text, I've skimmed it and read the discussion, and teixobactin sound quite promising. They haven't found any protein to which it binds, and they think it binds to an "Achilles's heel" in the outer cell wall. The method described to generate resistance was their most extreme attempt, so I assume they tried the fast way, and I can see why it didn't work. Ecologically, they believe there's little gene (e.g. plasmid) transfer between these soil bacteria and human pathogens, and the "30 year" bit came from experience with vancomycin, to which it has a lot of similarity. And they've done lots of tests for human toxicity and effectiveness in mammals. It's still early in the process, but a degree of fuss is warranted, especially due to their discovery method.
    - pcrh 12y ago
      Here are the pertinent bits regarding resistance, in summary it implies that spontaneous resistance will be difficult, But... "life has a way": >We were unable to obtain mutants of S. aureus or M. tuberculosis resistant to teixobactin even when plating on media with a low dose (4 X MIC [minimal inhibitory concentration]) of the compound. Serial passage of S.aureus in the presence of sub-MIC levels of teixobactin over a period of 27 days failed to produce resistant mutants as well (Fig. 2d, Supplementary Discussion) From the Supplementary information: >Cells were added to teixobactin present at 0.25xMIC, 0.5xMIC,1xMIC,2xMIC and 224xMIC. At 24 hour intervals, the cultures were checked for growth. Cultures from the second highest concentrations that allowed growth (OD600≥2) were diluted 1:100 into fresh media containing 0.25xMIC, 0.5xMIC,1xMIC,2xMIC and 4xMIC of teixobactin. This serial passaging was repeated daily for 30 days. Any cultures that grew at higher than the MIC levels were passaged on drug free MHA plates and the MIC was then determined by broth microdilution. No resistant mutants were obtained. This experiment was repeated, and produced the same negative result. In order to maximize the chance of obtaining a resistant mutant, we performed an additional experiment with very small incremental increases in the drug concentration. Cells were added to a series of tubes with small differences in the concentration of teixobactin (0.06xMIC, 0.25xMIC, 0.5xMIC, 0.75xMIC,1xMIC, 1.25xMIC, 1.5xMIC, and 2xMIC). At 24 hour intervals, cultures from the highest concentration that allowed growth to a minimum OD600 of 0.2 were diluted 1:100 into fresh medium containing 0.06xMIC, 0.25xMIC, 0.5xMIC, 0.75xMIC,351xMIC, 1.25xMIC, 1.5xMIC, and 2xMIC. This passaging was repeated for 27 days. Cultures that grew at levels higher than the MIC were passaged on drug free MHA plates, and the MIC was determined. For teixobactin, there were no mutants with an MIC greater than the parent S. aureus ATCC 29213.
- maurycy 12y ago
  What is the exact name for the survival mechanism you described?
  - hga 12y ago
    Errr, spontaneous mutation?? Selection pressure for such mutations that are still survivable for the bacteria? I just described a very rough screening method, pcrh quotes from the Nature article other extreme efforts tried. These don't produce specific types of mutations, they just discover if there are any "easy" ones. E.g. the E. Coli antibiotic I mentioned had to be transported across the membrane bacterium by a protein. The lab I did part of a summer's research was working with the enterobactin iron scavenging mechanism in E. Coli (https://en.wikipedia.org/wiki/Enterobactin https://en.wikipedia.org/wiki/Enterobactin). If grown in seriously iron free condition (e.g. glassware was soaked in HCl, and then bathed in deionized water for days), it would synthesize iron binding enterobactin and send it out into the environment, and there was a protein on the membrane surface that would accept the enterobactin+iron complex. This also turned out to be the protein that accepted this antibiotic into E. Coli. It appeared that some of the mutations that allowed this were either point or deletion mutations of that protein, either it was deranged or cut off in some location, or outright deleted (missing from the bacteria's set of genes in its DNA). So this survival mechanism is one of just not letting the antibiotic inside in the first place, which is how it appears teixobactin producing bacteria survive it. They appear to synthesize and expel it, and they don't have cell walls allowing it to get back in.
- Natsu 12y ago
  It's too bad there's no easy way to make resistance work for us, instead of against us. Like finding something else for these to infect, having them get resistance to the nasty bug, then using the same method to get rid of it.
  - eru 12y ago
    You might be interested in phage therapy. A phage is a virus that attacks bacteria. (https://en.wikipedia.org/wiki/Phage_therapy https://en.wikipedia.org/wiki/Phage_therapy)
  - gus_massa 12y ago
    Many of the antibiotics are made naturally by fungus to combat bacteria. Once discovered, we just create a synthetic method to prepare them, and perhaps improve the effectiveness and reduce the collateral effects. The canonical example is penicillin http://en.wikipedia.org/wiki/Penicillin#History http://en.wikipedia.org/wiki/Penicillin#History
danieltillett 12y ago
I am a microbiologist. It is not that you want to target basic cell structures, but you want to either target multiple systems, or target systems that have a large number of modular interactions. It is relatively easy to create/discover new chemicals that kill bacteria specifically, but if these new chemicals only target one specific component then the bacteria rapidly evolve resistance. All the good antibiotics we have interact with complex systems like ribosomes that are made up of multiple interacting modules. The reason we are having trouble finding new classes of antibiotics is that we are already have chemicals that target most of the interacting and essential cellular modules in bacteria. If you already are targeting 90% of all the possible targets you will find it very hard to discover any new classes of antibiotics. Of course the solution is not to worry too much about finding new classes and just keep tweaking the current antibiotics to keep ahead of the bacteria. The only problem with this strategy is that the economics of antibiotic development is totally broken so the pharmaceutical companies have in the main stopped spending money on finding new antibiotics. What we need to work on is a new way of paying for new antibiotic development.
- DennisP 12y ago
  It seems strange to me that we're willing to spend trillions of tax dollars on the military, but when it comes to the bacteria that attack us every day, we throw up our hands and just take whatever the free market finds profitable to provide.
  - hga 12y ago
    http://en.wikipedia.org/wiki/Public_good http://en.wikipedia.org/wiki/Public_good Plus drugs are one of the very most heavily regulated "free markets" in the US ... and as others have noted, there are laws like the Bayh-Dole Act (https://en.wikipedia.org/wiki/Bayh%E2%80%93Dole_Act https://en.wikipedia.org/wiki/Bayh%E2%80%93Dole_Act) which can make the process much more of a government-non-profit-corporate partnership. There is also a "Generating Antibiotic Incentives Now" (GAIN) in effect, with an bipartisan Antibiotic Development to Advance Patient Treatment in the works. So, no, we don't "just take whatever the free market finds profitable to provide", where "profitable" has "the visible foot" of the government strongly weighting one side of the balance scale. Not to mention very strong medical policy to restrict new novel antibiotics like this one to the cases where they're really needed.

hga 12y ago

So do the β-Lactam antibiotics (e.g. penicillin), but that doesn't stop a host of unrelated resistance mechanisms: enzymes that directly attack it, mutations to the protein(s) that are necessary for entry into the bacteria, and probably the pumps that actively remove various antibiotics. Given that this was discovered from existing bacteria, there's a significant chance nature has already done the first and last of those. The middle mechanism is likely possible for any bacteria, if you have enough to start with (there's nothing I could find with Google in a minute to describe teixobactin's transport mechanism). In general there was a rule of thumb when I was doing microbiology of this exact nature (an antibiotic created by some strains of E. Coli), if you exposed a million bacteria cells to a generic antibiotic, 1 would would survive due to a mutation (a useful number in microbiology, likely dead meat in the body). Streptomycin was more effective, 1 in a billion. ADDED: it's implied by the Nature abstract that the researchers have tried this general approach, that they were not able to find spontaneous resistance mutations in a couple of the standard nasties. But extending on the above thesis, ecologically, there's a respectable chance some bacteria out there have developed defenses. It's a jungle out there, and e.g. in your gut, that's why fungi and bacteria developed antibiotics in the first place. They aren't expending resources just to allow us to kill the inconvenient ones.

pcrh 12y ago
From the Nature article, the claim that resistance to teixobactin is hard is based on an attempt by the authors to induce resistance by culturing S. aureus or M. tuberculosis in the presence of sub-lethal concentrations of teixobactin for 27 days and seeing if resistant clones evolved. They did not observe any. That doesn't mean it's impossible, though. Plasmids for example are a source of resistance that doesn't require mutations. Edit: deleted incorrect information about b-lactamase.
- Fomite 12y ago
  No. Beta-lactams inhibit cell wall synthesis by binding with penicillin binding proteins and preventing their function. Beta-lactamase is a resistance mechanism against this family of drugs.
  - pcrh 12y ago
    You're correct, I'll correct my post.
- hga 12y ago
  [ Deleted β-Lactam stuff. ] Nature asked me for $$$ to read the article, so ... from your description, that's leaving out the hard, fast test of just culturing several billion of those, adding a lethal concentration and seeing if there are any survivors. Which is how I gather one found spontaneous transport mutations, at least circa 1977. The state of the art has likely improved, and these guys used novel microbiological methods to find the bacteria that produce teixobactin in the first place. ADDED: thanks to betatim's link to the full text, I've skimmed it and read the discussion, and teixobactin sound quite promising. They haven't found any protein to which it binds, and they think it binds to an "Achilles's heel" in the outer cell wall. The method described to generate resistance was their most extreme attempt, so I assume they tried the fast way, and I can see why it didn't work. Ecologically, they believe there's little gene (e.g. plasmid) transfer between these soil bacteria and human pathogens, and the "30 year" bit came from experience with vancomycin, to which it has a lot of similarity. And they've done lots of tests for human toxicity and effectiveness in mammals. It's still early in the process, but a degree of fuss is warranted, especially due to their discovery method.
  - pcrh 12y ago
    Here are the pertinent bits regarding resistance, in summary it implies that spontaneous resistance will be difficult, But... "life has a way": >We were unable to obtain mutants of S. aureus or M. tuberculosis resistant to teixobactin even when plating on media with a low dose (4 X MIC [minimal inhibitory concentration]) of the compound. Serial passage of S.aureus in the presence of sub-MIC levels of teixobactin over a period of 27 days failed to produce resistant mutants as well (Fig. 2d, Supplementary Discussion) From the Supplementary information: >Cells were added to teixobactin present at 0.25xMIC, 0.5xMIC,1xMIC,2xMIC and 224xMIC. At 24 hour intervals, the cultures were checked for growth. Cultures from the second highest concentrations that allowed growth (OD600≥2) were diluted 1:100 into fresh media containing 0.25xMIC, 0.5xMIC,1xMIC,2xMIC and 4xMIC of teixobactin. This serial passaging was repeated daily for 30 days. Any cultures that grew at higher than the MIC levels were passaged on drug free MHA plates and the MIC was then determined by broth microdilution. No resistant mutants were obtained. This experiment was repeated, and produced the same negative result. In order to maximize the chance of obtaining a resistant mutant, we performed an additional experiment with very small incremental increases in the drug concentration. Cells were added to a series of tubes with small differences in the concentration of teixobactin (0.06xMIC, 0.25xMIC, 0.5xMIC, 0.75xMIC,1xMIC, 1.25xMIC, 1.5xMIC, and 2xMIC). At 24 hour intervals, cultures from the highest concentration that allowed growth to a minimum OD600 of 0.2 were diluted 1:100 into fresh medium containing 0.06xMIC, 0.25xMIC, 0.5xMIC, 0.75xMIC,351xMIC, 1.25xMIC, 1.5xMIC, and 2xMIC. This passaging was repeated for 27 days. Cultures that grew at levels higher than the MIC were passaged on drug free MHA plates, and the MIC was determined. For teixobactin, there were no mutants with an MIC greater than the parent S. aureus ATCC 29213.
maurycy 12y ago
What is the exact name for the survival mechanism you described?
- hga 12y ago
  Errr, spontaneous mutation?? Selection pressure for such mutations that are still survivable for the bacteria? I just described a very rough screening method, pcrh quotes from the Nature article other extreme efforts tried. These don't produce specific types of mutations, they just discover if there are any "easy" ones. E.g. the E. Coli antibiotic I mentioned had to be transported across the membrane bacterium by a protein. The lab I did part of a summer's research was working with the enterobactin iron scavenging mechanism in E. Coli (https://en.wikipedia.org/wiki/Enterobactin https://en.wikipedia.org/wiki/Enterobactin). If grown in seriously iron free condition (e.g. glassware was soaked in HCl, and then bathed in deionized water for days), it would synthesize iron binding enterobactin and send it out into the environment, and there was a protein on the membrane surface that would accept the enterobactin+iron complex. This also turned out to be the protein that accepted this antibiotic into E. Coli. It appeared that some of the mutations that allowed this were either point or deletion mutations of that protein, either it was deranged or cut off in some location, or outright deleted (missing from the bacteria's set of genes in its DNA). So this survival mechanism is one of just not letting the antibiotic inside in the first place, which is how it appears teixobactin producing bacteria survive it. They appear to synthesize and expel it, and they don't have cell walls allowing it to get back in.
Natsu 12y ago
It's too bad there's no easy way to make resistance work for us, instead of against us. Like finding something else for these to infect, having them get resistance to the nasty bug, then using the same method to get rid of it.
- eru 12y ago
  You might be interested in phage therapy. A phage is a virus that attacks bacteria. (https://en.wikipedia.org/wiki/Phage_therapy https://en.wikipedia.org/wiki/Phage_therapy)
- gus_massa 12y ago
  Many of the antibiotics are made naturally by fungus to combat bacteria. Once discovered, we just create a synthetic method to prepare them, and perhaps improve the effectiveness and reduce the collateral effects. The canonical example is penicillin http://en.wikipedia.org/wiki/Penicillin#History http://en.wikipedia.org/wiki/Penicillin#History

danieltillett 12y ago

I am a microbiologist. It is not that you want to target basic cell structures, but you want to either target multiple systems, or target systems that have a large number of modular interactions. It is relatively easy to create/discover new chemicals that kill bacteria specifically, but if these new chemicals only target one specific component then the bacteria rapidly evolve resistance. All the good antibiotics we have interact with complex systems like ribosomes that are made up of multiple interacting modules. The reason we are having trouble finding new classes of antibiotics is that we are already have chemicals that target most of the interacting and essential cellular modules in bacteria. If you already are targeting 90% of all the possible targets you will find it very hard to discover any new classes of antibiotics. Of course the solution is not to worry too much about finding new classes and just keep tweaking the current antibiotics to keep ahead of the bacteria. The only problem with this strategy is that the economics of antibiotic development is totally broken so the pharmaceutical companies have in the main stopped spending money on finding new antibiotics. What we need to work on is a new way of paying for new antibiotic development.

DennisP 12y ago
It seems strange to me that we're willing to spend trillions of tax dollars on the military, but when it comes to the bacteria that attack us every day, we throw up our hands and just take whatever the free market finds profitable to provide.
- hga 12y ago
  http://en.wikipedia.org/wiki/Public_good http://en.wikipedia.org/wiki/Public_good Plus drugs are one of the very most heavily regulated "free markets" in the US ... and as others have noted, there are laws like the Bayh-Dole Act (https://en.wikipedia.org/wiki/Bayh%E2%80%93Dole_Act https://en.wikipedia.org/wiki/Bayh%E2%80%93Dole_Act) which can make the process much more of a government-non-profit-corporate partnership. There is also a "Generating Antibiotic Incentives Now" (GAIN) in effect, with an bipartisan Antibiotic Development to Advance Patient Treatment in the works. So, no, we don't "just take whatever the free market finds profitable to provide", where "profitable" has "the visible foot" of the government strongly weighting one side of the balance scale. Not to mention very strong medical policy to restrict new novel antibiotics like this one to the cases where they're really needed.