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A New Antibiotic That Resists Resistance

The British chemist Lesley Orgel had a rule: Evolution is cleverer than you. Antibiotic-resistant bacteria have repeatedly proven him right.

Since humans started making antibiotics for ourselves in the 1940s, bacteria have evolved to counteract our efforts. They are now winning. There are strains of old foes that withstand everything we can throw at them. Meanwhile, our arsenal has dried up. Before 1962, scientists developed more than 20 new classes of antibiotics. Since then, they have made two.

More, hopefully, are coming. A team of scientists led by Kim Lewis from Northeastern University have identified a new antibiotic called teixobactin, which kills some kinds of bacteria by preventing them from building their outer coats. They used it to successfully treat antibiotic-resistant infections in mice. And more importantly, when they tried to deliberately evolve strains of bacteria that resist the drug, they failed. Teixobactin appears resistant to resistance.

Bacteria will eventually develop ways of beating teixobactin—remember Orgel—but the team are optimistic that it will take decades rather than years for this to happen. That buys us time.

Teixobactin isn’t even the most promising part of its own story. That honour falls on the iChip—the tool that the team used to discover the compound. Teixobactin is a fish; the iChip is the rod. Having the rod guarantees that we’ll get more fish—and we desperately need more.

Bacteria have been fighting each other for billions of years before we arrived, so environmental microbes are a rich source of potential new antibiotics. The problem is that 99 percent of them won’t grow in lab conditions. So, why not bring the environment into the lab?

That’s what the iChip does. It’s just a board with several holes in it. The team fill the holes by collecting soil, shaking it in water to release any microbes, heavily diluting the sample, mixing it with liquid agar, and pouring the agar into the iChip. The dilution ensures that each hole, now plugged by a disc of solid agar, contains just one bacterial cell. They then covered the discs in permeable membranes and dunked the whole board into a beaker of the original soil. The microbes are constrained to the agar, but they can still soak up nutrients, growth factors, and everything else they need from their natural environment. And thus, the ungrowable grows. “We have access to things that haven’t been seen before,” says Lewis.

“The method has the potential to be truly transformative, giving us access to a much greater diversity of environmental bacteria than previously imagined,” says Gautam Dantas from Washington University in St Louis.

Among these new microbes, the team found one species that kills staph bacteria efficiently. It belongs to an entirely new genus and is part of a group that’s not known for making antibiotics. They called it Eleftheria terrae. It yielded a compound—teixobactin—that could kill important rogues like the bacteria behind anthrax and tuberculosis, and Clostridium difficile (which causes severe diarrhoea). The team exposed some of these microbes to low levels of teixobactin for several weeks, to see if resistant strains would evolve. None did.

“I thought: Aw, damn it,” says Lewis. “We discovered a detergent.”

Counter-intuitively, if you see a total lack of resistance, it usually means that you’ve discovered a compound so toxic that it’s never going to work in an actual human. Hence: Lewis’s dismay. But when his team applied the drug to mammalian cells, it wasn’t toxic at all. It seemed safe, stable in blood, and capable of protecting mice from lethal doses of MRSA (drug-resistant staph). Things were looking up.

Losee Ling from NovoBiotic Pharmaceuticals and Tanja Schneider at the University of Bonn showed that teixobactin works by withholding two molecules—Lipid II, which bacteria need to make the thick walls around their cells, and Lipid III, which stops their existing walls from breaking down. When teixobactin is around, bacterial walls come crumbling down, and don’t get rebuilt.

The drug also sticks to parts of both Lipid II and Lipid III that are constant across different species of bacteria. It’s likely that these parts can’t be altered without disastrous consequences, making it harder for bacteria to avoid teixobactin’s double-punch. This might explain why it’s so hard to evolve resistance to the drug.

This won’t work on every bacterium. Many of them, like E.coli, Salmonella, and Helicobacter, have another membrane around their cell walls that can deflect teixobactin. So does E.terrae—the microbe that makes the drug in the first place. That’s actually a good thing. Lewis says that many of the resistance mutations that defuse antibiotics originate the microbes that produce those drugs—after all, they must protect themselves. But since E.terrae is impervious to teixobactin, it doesn’t need any such mutations. It has no countermeasure for other bacteria to borrow. “It started looking to us like a fool-proof case of no resistance,” he says.

The existing antibiotic vancomycin also works by sticking to Lipid II, albeit to a different part of the molecule that changes more from one microbe to the next. It took 30 years for bacteria to start resisting vancomycin, and Lewis hopes that teixobactin resistance will take even longer to appear.

We are constantly in need of new antibiotics with novel mechanisms of action, especially ones that can evade known resistance mechanisms,” says Karen Bush from Indiana University. Teixobactin certainly fits that bill, but Bush is sceptical that it is as resistance-proof as it first appears. “Other agents have been studied in similar kinds of resistance selection studies as described in the paper.  Although those drugs had no demonstrable resistance under that set of conditions, more stringent selection procedures resulted in detection of resistant strains,” she says.

Laura Piddock, a microbiologist at the University of Birmingham and leader of Antibiotic Action, adds that other environmental bacteria might harbour countermeasures to teixobactin. “To be sure that resistance to this new antibiotic is unlikely to occur in the clinical setting, bacteria isolated from the same environmental niche should be screened for teixobactin-resistance conferring genes,” she says in an email.

Meanwhile, Lewis’ team are doing more tests with teixobactin in other animals, with a view to eventually getting FDA approval. They’re also trying to tweak the compound and make it more soluble, which would allow them to give people higher doses. And, of course, he will continue to use the iChip to identify even more potential drugs.

Will we ever return to the glory days of antibiotic discovery?

“There’s no doubt in my mind that we’ll do exactly that,” he says.

Reference: Ling, Schneider, Peoples, Spoering, Engels, Conlon, Mueller, Schaberle, Hughes, Epstein, Jones, Lazarides, Steadman, Cohen, Felix, Fetterman, Millett, Nitti, Zullo, Chen & Lewis. 2015. A new antibiotic kills pathogens without detectable resistance. Nature. http://dx.doi.org/10.1038/nature14098

16 thoughts on “A New Antibiotic That Resists Resistance

  1. Really exciting! Working in the antibiotic field, I take any claim of resistance-evading antimicrobials with a large heaping of salt and remember the words of a sage Jeff Goldblum: “Nature finds a way”.

    Yet, a compound that works this way really does show a lot of promise. New compounds that hit universally-conserved targets probably won’t be easily discovered, but this shows it’s possible. Very exciting!

  2. I’m greatly encouraged by this article. A doctor told me a little over a year ago that antibiotics were becoming less effective and new ones were not being developed. Due to a medical condition, I am highly vulnerable to UTI’s and started to resign myself that someday nothing would work to kill the bacteria. I have developed an allergy to one and it seems plausible others will follow.

  3. The time it takes for bacterial to evolve resistance would not be expected to correlate only to how hard it is to evolve, but also how much exposure the bacteria get to the antibiotic. ie how many generations of how many cells get a chance to “test” mutations against the antibiotic. Put enough batters up against the ace pitcher and sooner or later one of them hits the home run no matter how good the pitcher is.

    Overuse and abuse of antibiotics is thus the single biggest culprit that promotes the evolution of resistance, and the volume of antibiotic use has simply skyrocketed in recent times. The total amount of cell-generation-exposures that used to take decades to accumulate now take just years. Maybe months.

  4. Is amazing how much press this potential drug — 5 or 6 years from getting to market if it passes muster — gets when there is a novel agent, Brilacidin (owned by Cellceutix), about to enter Ph III for ABSSSI. The compound, part of a first and only of its kind class of antiinfectives called defensin-mimetics, is the real deal. Based on Brilacidins mech of action resistance is unlikely to develop, ever. FDA already has granted it QIDP status for ABSSSI. Read more below.
    This is where the media should be focusing their wordage as to tackling the (legit) Superbug fear factor.



  5. Going back to the baseball analogy, what happens when the batters are up against a highly-advanced pitching machine capable of delivering the ideal strike at over 200 mph every time? IOW, a practically unhittable ball? This is what teixobactin represents. No matter how strong the batter may be, a heater that fast is likely to knock back even an aluminum bat on contact and probably sprain or break the batter’s wrists. Evolving a body capable of properly hitting back a 200mph heater is likely to result in side effects that can make a player less effective on the field. Think a stiffer wrist. It may be strong enough to handle the impact of the ball, but of necessity it becomes less maneuverable, and the whipping action of a wrist is key to making a fast throw needed to either pitch or make a long-distance play. To gain that ability back while keeping the stiff wrist would take some other, non-novel evolution of the arms or such. That’s the kind of evolutionary leap a gram-positive bacteria would need to defeat teixobactin, and as the article notes, attempting such a leap runs the serious risk of dead-ending from side effects.

  6. I agree that the most interesting part of this story is the new tool to culture previously uncultivatable soil bacteria. I don’t see anything particularly exciting in teixobactin itself – it has a similar mode of action to vancomycin and particularly oritavancin which was recently approved by the FDA but is similarly restricted to Gram positives which is not where the need to new antibiotics lies.

  7. There is an urgent need for newer antibiotic due to developing resistance. The resistance is completely a problem created by improper medication intake. The newer molecule should be used very carefully and in restricted manner. There are number of guidelines suggesting rational use of antibiotic depending upon infection but they are not followed appropriately. These guidelines are available freely and easily on databases like http://www.treatmentguideline.com to download.

  8. Hello,
    The search for new useful antibiotics is very important, especially given the fact that pharma thinks it too expensive. We discovered and characterized a compound that kills all bacteria tested, including MRSA and bad boys, and used appropriately, can make possible the search for new antibiotics.
    In 2012, we discovered, entirely by chance, and reported that creatinine (not creatine), a lowly and normal waste product molecule from vertebrate metabolism thought to have no biologic activity, is a superb, broad spectrum antibacterial agent. It stops replication and kills all Gram positive and negative bacterial species tested as well as drug-resistant strains, bacteria in fecal and soil samples. Being a naturally occurring waste product, it cannot be used internally such as standard antibiotics (as it would be voided) but it could certainly be used externally as one might use a triple antibiotic ointment. However, creatinine would be superior, as it has no problems killing all, even drug resistant, bacteria. We have found no evidence that bacteria can become resistant to creatinine.
    In 2014, we expanded this work to show that new antibiotics can be discovered using creatinine’s activity against bacteria. A problem when using environmental samples is the huge bacterial load that must be suppressed in order to find slower growing fungi to assay for potentially new ‘standard’ antibiotics. Creatinine does this excellently, as it does not inhibit fungi outgrowth. We show evidence of a new antibiotic that functions against Gram positive and negative species as well as drug resistant bacterial strains.
    Creatinine is cheap, safe, can be added to existing creams/lotions without problems, is more efficient than standard antibiotics, and could be used like any other over-the-counter antibiotic ointment available today. Unlike antibiotics with long work up times and costs, creatinine also could be used readily in poor parts of the world. It has other potential clinical, veterinary and industrial applications too numerous to mention.
    Scientific literature is like a swamp, deep and full of very interesting things if you look adequately and not merely in the most prominent spots. You can access the papers mentioned as shown here:
    J Antibiotics (2012) 65:153-156. Epub 2012 Feb 1. “Creatinine inhibits bacterial replication.” McDonald T, Drescher KM, Weber A, Tracy S.
    J Microbiol Methods (2014) 105:155-61. Epub 2014 Aug 2. “A novel, broadly applicable approach to isolation of fungi in diverse growth media.” Smithee S, Tracy S, Drescher KM, Pitz LA, McDonald T.
    Steven Tracy, PhD
    Department of Pathology and Microbiology
    University of Nebraska Medical Center
    Omaha NE 68104

  9. Just thought as I did my PhD on glycopeptides I’d add something to the vancomycin resistance story. The reason we used to cite when I was working on them was that resistance took so long to form was the drug was toxic and therefore not used. Many of the original preparations had significant side effects e.g. ‘red man syndrome’. Better preparation avoided some of the side effects (it was partially caused by a contaminant) but still it’s not something you can give in a pill, it has to be on drip.

    So in reality the resistance to the appeared quite quickly after it started being use therapeutically. Which isn’t a surprise as the gene cluster for resistance is quite small and IIRC on a transposon.

    My PhD is here and it might be in the introduction but it’s been a few year – http://evath.net/research/downloads/thesis.pdf

  10. Glad to see such great progress with soil bacteria, like we have hypothesized before (ISME: The quest for a unified view of bacterial land colonization) that soil bacteria are the real arsenal worth more attractions.

  11. This ingenious discovery is amazing! Very glad that it happened during our time. To think that it is taken from a simple and accessible source, soil. And that drug resistance will be years away. I am excited that it will be out in the market soon. Congratulations! Hopefully, it will be used cautiously.

  12. This is very exciting news from the antibiotic research world..Am an epidemiologist and i can say that we are running very low on viable anti infectives..This to me is great news and Dr Lewis and his team will do the world a favour if only they can speed toward FDA approvals..!!

  13. The Federal government is the biggest inhibitor of our pharmaceutical growth industry and the solving of complex medical dilemmas. The FDA is run by bureaucrats with medical degrees who would be poor physicians, therefore they do to government. This is analogous to poor lawyers going into politics. This lends itself to poor outcomes in government, as we see everyday and poor outcomes in the private sector because of increasing government intervention. Tell someone who is going to die shortly it will be 5 years before we can test the drug on humans. It’s not ethical, tell that to a dead person. The less government we have in our lives the better. Without government the private sector will police itself and in the process become more efficient.

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