Low-Hanging Fruit: Nyekulturny

A fundamentally new antibiotic, teixobactin, has been discovered, that may be useful against MRSA and other Gram-positive bacteria.  It works in mice.  A good thing, since antibiotic resistance is increasing common, while pharmaceutical companies don’t have much interest in developing antibiotics, since they are curative.

The methodology is what’s really interesting.  Kim Lewis and Slava Epstein sorted individual soil bacteria into chambers of a device they call the iChip, which is then buried in the ground – the point being that something like 98% of soil bacteria cannot be cultured in standard media, while in this approach, key compounds (whatever they are) can diffuse in from the soil, allowing something like 50% of soil bacteria species to grow.  They then tested the bacterial colonies (10,000 of them) to see if any slammed S. aureus – and some did.

I get the impression that many people believe that these bacteria cannot be cultured – the word “unculturable” is often used.  Actually, although they have not been grown in the lab, that hardly means it is impossible to do so: it’s just that that no one has figured out how. Microbiologists, over the years,  have figured out the  special dietary requirements of many organisms.  With honorable exceptions like Lewis’s work, advances in this area seem to have slowed down.

I could be wrong, but I wonder if part of the explanation is that microbiology – the subject – is in relative decline, suffering because of funding and status competition with molecular biology and genomics (sexier and less useful than microbiology) . That and the fact that big pharma is not enthusiastic about biological products.

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24 Responses to Low-Hanging Fruit: Nyekulturny

  1. A Fan says:

    One important thing you failed to mention is that one of their more promising antibiotics functions by latching onto a bacterial structure that seems to be less liable to mutation than most antibiotic targets. I heard this on NPR last night. (I listen in on the old theory that it’s good to know your enemy and NPR does some pretty decent coverage of issues that don’t threaten their ideology.)

  2. JayMan says:

    I was waiting for your take on it.

  3. It’s not just big pharma. Small pharma isn’t interested in a lot of these new types of drugs either. In fact, almost no one is interested in things they don’t benefit from that benefit mankind. You have noted many times the lack of evidence for group rather than individual fitness in selection.

    • gcochran9 says:

      Well, it’s conceivable that some of the big pharma execs are human and subject to infectious disease.

      Big pharma used to develop antibiotics – maybe they were unsophisticated back then?

      NIH has about 30 billion a year to throw around: be nice if they did more useful things like this that tend to fall thru the corporate cracks. Or any useful things.

      • Rum says:

        It is only half right to speak of antibiotics these days as “curative”. They are crucially important as preventatives. Modern joint replacement surgery (and many other new procedures) are dependent on effective antibiotics given prior to surgery to suppress infection from likely agents, especially s. aureus. If Vancomycin stopped being reliable a multi-billion dollar slice of the health care business would stall out.
        The best way to make big money in this industry is to solve the needs of the players with money. Which is a subtly different thing than directly curing patients illnesses.

        • gcochran9 says:

          Reminds me of when the guys doing ancient DNA found they could do much better by running the drill slowly. Run it fast and you smell stuff burning: bye-bye DNA.

  4. Here’s another article about finding out how to culture microbes that are “unculturable” (a different piece of work):

    http://schaechter.asmblog.org/schaechter/2014/12/the-great-plate-count-anomaly-that-is-no-more.html

    It falls even more in the “wait, why didn’t they try that a long time ago?” category. Granted, there are a lot more variables you can change in biology, and so people get used to just sticking with some recipe, but still…

    • Anonymous says:

      Using gellan gum as solidifying agent is not a new trick- I myself do use it since 2005 when I started to work with thermoplasma, an archaeon needed 60C and pH:1 for growth (agar-agar could not solidify at this pH). The main problem in the cultivation of the components of natural microflora is the altered growth rate of the microbes belonging to different microbial taxons (e.g. generation time for coli ~20 minutes, for thermoplasma it needs up to 10 hours). Exotic tricks for support the slow growing ones needed for success, as the first basic step isolating a microbial strain is the generation of axenic culture- obtaining a single colony on the solid medium.
      On the other hand, in conventional microbial media the available carbon sources (sugars, peptides, amino acids) are three order of magnitude higher than in the real life. Even agar-agar or gellan gum contain carbon sources inhibiting the chemolithotropic microbes- in this case silica based solidifying agent do the trick.

  5. strongsloth says:

    In the past it has often appeared, based on proven reserves, that resources such as metals and oil have been in danger of running out even though they haven’t been. One of the reasons it looked that way is that it costs a lot of money to explore and survey deposits. It’s just not worth doing it while there are existing supplies.

    Perhaps antibiotics are a similar case. Companies haven’t surveyed more than a fraction of possible sources and perhaps they won’t until we reach a point where existing antibiotics are exhausted to a point where it makes commercial sense.

    There are a few important differences though.
    1. Antibiotics have a limited patent period, which makes finding them before they are really needed an especially unwise commercial decision.

    1. While a new iron ore deposit is a perfect substitute for an old one that is not true of antibiotics which have some variation in uses. That makes finding them while we have lots of other, working antibiotics slightly less silly than if they all had exactly the same impact.

    On the other hand. Perhaps this discovery is a sign that we are getting to the point where looking for more makes commercial sense.

    • Sean II says:

      Indeed. When I talk to my friends in Big Pharma and Big Ag, I’m often surprised to discover how speculative and non-commercial some of their projects sound.

      I’ve told them this would irritate micro-economists, but they don’t seem to care.

  6. BurplesonAFB says:

    My understanding is that the really important part is that we don’t tell the Indians about it. Confirm?

  7. sprfls says:

    Bravo on the title Dr. Cochran. 🙂

  8. M Simon says:

    …the fact that big pharma is not enthusiastic about biological products.

    Look at how hard they fight cannabis. A multi-category killer. It looks like it might be effective against some cancers. Maybe all of them.

    http://www.cancer.gov/cancertopics/pdq/cam/cannabis/healthprofessional/page4

    And then there are the anti-depressant properties. The list of problems it could treat is very long. The ‘net is rife with anecdotes. Our government protects the pharma companies by keeping it schedule one. “No medical use” – nonsense on stilts.

    • gcochran9 says:

      I think medical marijuana is bunk. Something potheads would like to be true. Since there are a lot of them, obviously it IS true, especially to politicians.

      The odds that any given plant is medically useful, in the sense of being efficacious and safe (more so than alternatives) is one in thousands, at best. Even then, in most cases you’d have to extract and purify the relevant active ingredient, rather than smoking the plant or baking it into brownies.

      “the net is rife with anecdotes”. What could be possibly be more convincing than that?

      • Anonymous says:

        This has been a central net topic of M Simon’s for a decade, anyway. I don’t know much about medical marijuana, though we have psych patients all the time insisting they need it. I do know a bit in a narrow area, however: If you have a psychotic illness, marijuana will make it worse enough that you might despair of ever recovering. That really should be enough for everyone to keep it at arm’s length – especially if you have any blood relatives with a psychotic illness, or any paranoia, even if it is non-psychotic.

        It’s not the worst thing out there, certainly. It is anxiolytic. But paranoia is a very bad side effect – bad enough that you don’t want to increase your chances of having it. Bob Drake, a researcher at Dartmouth’s medical school, once answered a first Q&A after a presentation with “Well, we’ve got an entire generation of psychiatrists who smoked a little in college and now think it’s dangerous. That tells you that a little probably doesn’t hurt you that much. It also tells you that the dangers must have made it over a pretty high bar to convert that many users.”

        • M Simon says:

          True about me and my studies. A decade’s worth at least.

          And your point about cannabis and psychosis is not entirely correct. CBD has shown promise for schizophrenia. The studies were done in Germany. I would agree that THC is not a good thing for people with psychosis.

          However the experiment has been running uncontrolled for 40 years now and we should have expected to see a spike in psychosis if cannabis is a trigger. No such spike is in evidence.

          BTW I don’t think psychiatrists are evidence of anything. My experience is that most of them are crazier than most of their patients. Which may actually back up your point. Cannabis is contraindicated for them. Generally.

          Another interesting fact I’d like to see looked into. The body’s endocannabinoid production peaks in the 15 to 25 age range (roughly). Cannabis consumption also peaks in that age range. No one knows why.

          And speaking of mental problems. We have lots of anecdotal reports that cannabis helps with PTSD where no other drugs work or the side effects of the other drugs are more extreme. The government has been stalling on proper studies for years. They just don’t want to let go of the cannabis they produce. I did read recently that that the government has upped the production of cannabis by a factor of 30 IIRC. Perhaps they intend to support some of the studies that are needed.

          As to paranoia? I have read the reports. But I’m not convinced that fear of jail time is not in whole or at least in part responsible. And it is also possible it is a set and setting problem. No proper studies have been done. In any case the effect seems transient. Stop using and the paranoia goes away.

          And I must ask. Why be anon? I use my own name.

      • Sean II says:

        I expected you to be a big fan of pot, if only because it’s such a widely-recognized example of rapid selection. Potency’s increased so fast old stoners are complaining.

        This yields a pretty good slogan: “Even degenerates can understand the power of genes, so…what’s your excuse?”

      • kot says:

        Exactly, medical CBD is great, medical pot not so much.

    • There is a funny thing about true medical marijuana. I’m talking about the weed that has been specifically bred to have very low levels of THC and higher levels of the supposed healing chemical CBD. It doesn’t sell. Yep, it just just sits there on the shelf of the stores in Colorado. All the “medical marijuana” that they do sell has extremely high THC levels. I don’t have a dog in this fight but it stands to reason that if medical marijuana had a real market for non stoners who need it for medical reasons then they would be buying it.

      I’m basically pro legalization of most drugs, we can tax them through the roof bringing in much needed revenue, we can stop the horrific narco business south of our border, and some of the seriously destructive users can be guided to real doctors whom can dope them up in a far less destructive fashion. But we have an actual real live experiment going on in Colorado right now testing if a need for actual medical marijuana exists and so far the answer appears to be no.

  9. Microbiologists do spend time learning how to culture very strange microorganisms. My wife’s master’s thesis depended on being able to culture bacteria that broke down tolune and TCE for energy. She was able to do this, although it is a bit of a challenge. Her late advisor specialized in extremophiles of all sorts. Things like this are useful because you can use bacteria like this to clean up chemical spills in groundwater, and bacteria work cheap.

    My wife also confirms that micro is far less sexy than genomics, although perhaps the luster is beginning to fade on genomics now. That doesn’t make the job prospects in micro any better, so she switched from growing bacteria to killing them, which pays better.

  10. Timtoc says:

    Another factor in the failure to develop antibiotics by Big Pharma is the rapidly spreading concept of Antibiotic Stewardship. In previous new antibiotic roll outs, the industry could promote the new antibiotic like the cephalosporins and suggest their use for all bacterial infections that they proved even a tiny bit more effective than the penicillins and at a much greater cost for patients and profit for themselves. In these days of antibiotic shortages, a new drug will be restricted by insurance formulary and by stewardship considerations. Some university hospitals have hired infectious disease doctors who review all antibiotic use. Others use nurses. There are often considerable economic savings as the newest drugs are very expensive. So, from the Pharma point of view, there are barriers for new antibiotic entry that are not there for other drug classes. Also, in the two of the antibiotic classes that were introduced, there was significant product safety variability that led to multiple product withdrawals in the quinolones and ketolides. So, relatively higher risk of losing the new drug investment and barriers to entry add to the factors mentioned.

  11. sainchuck says:

    what do you think about phage therapy?sounds expensive

  12. AKAHorace says:

    In the initial period when most antibiotics were discovered (1940s to 80s), researchers used relatively simple method of cultivating the 1-2% of bacteria that could be cultivated using standard methods. The decrease in discovery was partly because these methods no longer turned up anything new.

    The reason that researchers did not work more on developing better cultivation conditions was that there were several alternatives that seemed promising:

    -using the old methods but scaling them up so that instead of screening thousands of bacteria
    you were screening 10s of millions of bacteria. There were thought to be novel but very rare antibiotics. Not very glamorous, but it seemed practical with robotics. (Google Richard Baltz for more info)

    -a switch from natural products to synthesizing chemicals randomly and screening for activity (e.g. the tea bag method). This did not work but kept people busy for a decade.

    -metagenomics. Rather than figuring out how to grow uncultivatable bacteria, take DNA out of the whole community and put it into bacteria that you can grow in the lab. This work is continuing but there are problems of DNA extraction from soil (you DNA has to be clean and a lot longer than your gene of interest), screening the DNA for genes of interest (you want DNA from a community where as much of the genome of the bacteria is devoted to making antibiotics) and expressing this DNA once you get it into your E.coli in the lab. Google Sean Brady to see ;good examples of how this is going.

    The advantage of metagenomics was that once you got it to work you could use it on a lot of different targets. While there were examples of people using new cultivation methods to find new bacteria, these methods often only found a small fraction of the uncultivatables. Metagenomics had the potential to explore the genomes of everything out there. This latest paper says that they can cultivate a large fraction of the uncultivatables and is important for this alone.

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