May 30 2017

Superantibiotic for Superbug

enterococcus_faecalis-splImagine a day where you get a bacterial infection, and the doctors tell you that there is no antibiotic which is effective against this bug. It is resistant to everything we have. They can give you supportive care, but the infection just has to run its course and may be fatal. For this reason hospitals have to take extreme measures to prevent the spread of infection – disinfecting and wearing disposable protective garments each time they enter a patient’s room. This is already the case for patients with certain kinds of exposures and infections.

This is a serious concern, not hype like most of the doomsday scenarios the press likes to scare you with. Bacteria are slowly (or sometimes not that slowly) evolving resistance to our antibiotics. Even worse, bacteria have loops of DNA called plasmids which they can share with each other. Those plasmids might contain the code for resistance to one or more antibiotics. The more we use antibiotics, the more selective pressure there is for resistance.

The two main things we need to do to avoid a “post-antibiotic era” includes first uses antibiotics as smartly as possible. Use them only when necessary, use narrow-spectrum antibiotics when possible, and complete all courses of antibiotics so all the bacteria are killed.

The second thing we need to do is develop more and better antibiotics. Attacking bacteria using new mechanisms is especially useful. Ideally these antibiotics would be resistant to resistance – they would attack a vulnerability in the bacteria that they cannot easily evolve a defense against.

Even these methods, however, seem like they only delay the inevitable. There are only so many ways to kill a bacterium or stop it from reproducing. Further, they reproduce quickly in vast numbers which means there are lots of opportunities for random mutations to emerge that by chance offer resistance. I do wonder what the really long-term solution will be. Will we have to take certain antibiotics out of use for a few decades to allow resistance to fade? How desperate will the situation get?

My hope is that we will develop new antibiotics and new methods for killing bacteria that are immune to resistance. I am a techno-optimist, but we cannot count on technological breakthroughs. They are unpredictable.

A New Superantibiotic

Scientists are reporting on a new antibiotic, actually a tweaked old antibiotic, which looks promising. This will not be the ultimate solution to the antibiotic resistance problem, but it will buy us some more time if it works. The antibiotic is a modified version of vancomycin. One of the most worrisome “superbugs” is called VRE – vancomycin resistant enterococci.

Vancomycin works by inhibiting cell wall synthesis in gram-positive bacteria. In addition it alters cell wall permeability and RNA synthesis. Vancomycin is bacteriocidal, meaning it kills bacteria. Some antibiotics are bacteriostatic, meaning they don’t kill them outright but prevent their reproduction and give the immune system a chance to do its job.

Researchers at Scripps have made three chemical changes to vancomycin to make a deadlier version. The first change makes the primary action of the drug, preventing cell wall synthesis, 1000 times more potent than current vancomycin. This overcomes current resistance to vancomycin.

They also made two changes which add additional mechanisms by which the drug kills bacteria. This is potentially important because it means this one drug will kill certain bacteria by three separate mechanism. This makes it more difficult for bacteria to evolve resistance by chance, because any one bacterium would have to have three beneficial mutations.

When tested against 50 rounds of bacteria, the drug retained “nearly full potency.” While this sounds encouraging, I note it was only “nearly” full. You can ask Nearly Headless Nick from the Harry Potter world how significant the word “nearly” can be.

We know from other experiments, like Richard Lenski’s experiments, that bacteria can evolve traits that require multiple mutations, it just takes longer. So, while this is definitely encouraging, I would not assume that the development of resistance to this triple-mechanism antibiotic cannot emerge, only that it will take longer to emerge. We can avoid resistance by using the antibiotic sparingly and smartly.

The drug so far has only been tested in-vitro. It has not been tested in animals or people. That means we are 5-10 years away from this drug being approved, if it makes it through clinical research. The chemical changes may have also given the drug unwanted properties, and maybe even increased its toxicity to humans, so we have to do the research.

I really hope it works out, though. I also hope that pharmaceutical companies are putting the proper resources into researching new antibiotics. The Scripps approach also seems promising – taking existing antibiotics and tweaking them to make them more potent and overcome resistance. I wonder how much untapped potential there is in this approach.

We are basically in an arms race with bacteria, and they are winning. They are steadily gaining ground on our antibiotics, and we are not researching new drugs fast enough to keep up. While this potential new drug is encouraging, we need to do more.

21 responses so far

21 Responses to “Superantibiotic for Superbug”

  1. RickKon 30 May 2017 at 8:28 am

    Have others run across the argument from the anti-science crowd that “superbugs” are actually more virulent than their pre-antibiotic ancestors? The narrative is: science created superbugs, and if science had left well enough alone, we’d be just fine today.

  2. SteveAon 30 May 2017 at 8:50 am

    RickK: “Have others run across the argument from the anti-science crowd that “superbugs” are actually more virulent than their pre-antibiotic ancestors?”

    I’d love to drop these idiots into a medieval hospice and see their reaction to the vast array of nastiness on display. Always remembering that they wouldn’t see the most serious cases, since they would have dropped dead on road.

  3. Michael Finfer, MDon 30 May 2017 at 9:18 am

    Drugs like this one will buy us some time, but not that much time.

    There was an article in Science a few years ago titled “Antibiotic Resistance is Ancient.” That group sequenced DNA from 30,000 year old permafrost in Siberia and found a vancomycin resistance gene. This means that new genes did not have to evolve to give rise to antibiotic resistance, something that presumably takes a long time. Instead, we are most likely looking at genes that were preexisting and were repurposed by evolution, which seems to be a common story. My take on this is that it won’t take evolution very long to tweak the existing vancomycin resistance genes to provide resistance to this drug, assuming that it even turns out to be safe to use in humans.

    We need drugs with novel mechanisms of action. They should last us several decades. They, unfortunately, are not that easy to develop.

  4. tb29607on 30 May 2017 at 9:59 am

    Rickk,

    While in general I agree with SteveA, there has been recent emergence of a multi-drug resistant Staphylococcus aureus which was first noted in Texas, has been spreading to the rest of the U.S., and seems to be more invasive. At least in kids, not sure if the same is true for adults. Numbers are small, so studies are a few years out, but at conferences all of my colleagues agree that we are seeing more of these disseminated Staph infections.

    Hopefully this modified and more effective Vancomycin does not help farm animals grow bigger.

    I also think the most glaring evidence of antibiotic overuse is the exsistence of vancomycin Dependent enterococcus (has to have vancomycin present in order to grow).

    Antibiotics are overused and until patient satisfaction scores are no longer a part of physician reimbursement, the overuse will get worse, not better.

  5. Kawarthajonon 30 May 2017 at 10:58 am

    It seems like viruses might be the answer, since they, too, can evolve and adapt along with the bacteria they infect. Having no science background, my thoughts on this subject may be naive and unobtainable.

  6. edamameon 30 May 2017 at 11:02 am

    Naive question: why not fight them with biological warfare instead of chemical warfare? Couldn’t we engineer an active virus that is benign to us, but will beat the crap out of the bacterium? Is the problem that the bacteria would evolve so fast it would be ridiculously cost prohibitive? Or is the problem that the virus might not stay benign to us?

  7. edamameon 30 May 2017 at 11:02 am

    Kawarthajon you beat me to it! 🙂

  8. Karl Withakayon 30 May 2017 at 11:47 am

    Kawarthajon & edamame,

    Do you want the zombie apocalypse? Because that is how you get the zombie apocalypse. 🙂

  9. edamameon 30 May 2017 at 12:07 pm

    So it turns out that using bacteriophages (viruses that infect bacteria) is an extremely promising active research area that might work for some strains of bacteria. You could even use them to ‘rewire’ bacteria so they are no longer antibiotic resistant. Check this out:
    http://www.pnas.org/content/112/23/7267.abstract

    IOW Kawarthajon and I should start a biotech company. 😛

    Zombies R Us

  10. Kawarthajonon 30 May 2017 at 12:17 pm

    Karl, yes, yes I do want a Zombie Apocalypse! If it’s anything like the video games, it would be awesome! Got my shotgun and machete ready by the front door waiting for it to happen! 😉

  11. Kawarthajonon 30 May 2017 at 12:18 pm

    Edamame, let’s get started on our biotech asap! 🙂

  12. Kabboron 30 May 2017 at 12:44 pm

    It is funny because prior to reading the comments I was going comment that viruses are a potential solution.
    I also want to ask the question: Does increasing the number of mechanisms for defeating the bacteria potentially water down the individual mechanisms? I imagine that it all comes down to dose, but it would be unfortunate if the different mechanisms interfere with each other in any way. It would be kind of like stopping your regimen early in terms of making the bacteria more resistant by weeding out the weak ones.

    Along the virus line of thinking, is there any way we could use viruses to make our immune system more responsive to specific bacterial infections? Basically programing the cells to kill the unwanted bacteria more effectively? That’s probably several steps beyond practical, but another potential future avenue.

  13. Kabboron 30 May 2017 at 12:50 pm

    Also, I’m one of those silly people who do not want the zombie apocalypse because statistically speaking I would almost certainly be a zombie. Also I rather enjoy having living friends and family, and a society to live in. I understand I’m an outlier on that one.

  14. edamameon 30 May 2017 at 1:14 pm

    Kabbor the new CRISPR gene splicing technology can do anything you want, and with zero consequences, so definitely it can do what you are asking. 🙂

  15. Kabboron 30 May 2017 at 2:00 pm

    Excellent. Finally someone who doesn’t overpromise on technology! I’ll take my spoil-free self-replenishing pizza to go!

  16. tb29607on 30 May 2017 at 3:59 pm

    Kabbor,

    Making the immune system more responsive to specific bacteria sounds remarkably like immunization.

    The problem with using viruses for most things is that the immune system is remarkably good at filtering out foreign proteins. So bacteriophages are typically only effective for bacterial infections in skin or wounds (I think Russia has the most experience with this). I remember reading a while back that phages were being tested for throat infections but Streptococcus pyogenes (which causes strep throat) does not develop resistance to penicillin so I don’t think that research went anywhere.

  17. jimvic48on 30 May 2017 at 4:46 pm

    Steve,

    I would like to know your thoughts about antibiotic use in animal feed. It seems to me one could hardly come up with a better way to develop widespread resistance and that our efforts noted by you above are largely subverted by this continued practice. I presume it will be very hard to change this due to certain lobbies in our country, however. I read an account in a book about antibiotic resistance some years ago of a new drug being brought out in Germany. When it was tried on the first volunteers, they had resistance, which surprised the researchers. It turned out, according to the account, that they were farmers and their cattle had been fed with antibiotics added to their feed and they were similar enough to the new antibiotic being developed that they already had resistance even though they had never been exposed to this antibiotic before.

    Jim

  18. BBBlueon 30 May 2017 at 9:13 pm

    Are super bugs super because they are antibiotic resistant or because the are more virulent? It’s the former, no?

  19. Sarahon 30 May 2017 at 11:13 pm

    If we could prototype and test antibiotics more rapidly, that might help, but no approach I’ve heard of so far.

  20. almostmedicineryon 31 May 2017 at 5:48 am

    “This means that new genes did not have to evolve to give rise to antibiotic resistance, something that presumably takes a long time.”

    While on one hand, all genes are tweakings of previous genes (or tweaking of non-coding sections of DNA), the most likely reason that new genes didn’t have to evolve when we started using Vanco was that we didn’t invent Vanco. Like many antibiotics we just found some bacterium/fungus that had developed that antibiotic over many thousands of years in a war against another bacterium. And that bacterium also had the same amount of time to develop the resistance genes.

    It is reasonable to think that resistance genes would be more likely to develop from scratch if the antibiotic was entirely synthetic since it’s concept stage.

  21. Kabboron 31 May 2017 at 8:28 am

    tb29607,

    Yeah you are probably right. I could see how using viruses to get things done in the body could be problematic. In addition to the initial difficulty in applying the viruses, developing immunity to your life-saving viruses would be a major issue. Is there such a thing as cannibal bacteria? If we could use bacteria that only eat other bacteria it would be a somewhat self-limiting mechanism that could counter-evolve when the bacteria evolve. Just make these ones weak to conventional antibiotics so they are disposable.

    Then we swallow some paramecium to eat the bacteria, amoebas to eat the paramecium and live shrimp to eat the amoebas. It’s just sound science.

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