Teixobactin kills pathogens without detectable resistance

Published on April 21, 2015   36 min

Other Talks in the Series: Antibiotic Resistance

Other Talks in the Series: Small Molecule Drug Discovery

Other Talks in the Series: Topical Talks

I am Kim Lewis, Professor of Biology at the Department of Biology at Northeastern University in Boston. I'm also director of Antimicrobial Discovery Center, and I will be telling you today about teixobactin, a new antibiotic that we discovered, and how teixobactin kills pathogens without detectible resistance.
So I'd like to place our finding into the general context of what is happening in the field of antimicrobial discovery, and I will also spend some time explaining how we got the compound. So I'll tell you about our discovery platform. But let me start indeed with where we are with antibiotic discovery. We once had a golden era of antibiotic discovery. As you see here from approximately the 40s and through the 60s, the major classes of antibiotics have been discovered, and most of them came from mining of soil microorganisms. That platform was developed by Selman Waksman of Rutgers University who essentially elaborated on the original finding of Fleming discovered penicillin. So Fleming's case, there was a Petri dish with staph bacteria on it that was left carelessly opened, and a spore of a fungus, a penicillin fungus settled on that Petri dish, and Fleming when he came to work the next day, he discovered that there was a zone of growth inhibition around the cone of the growing fungus. So that was the beginning of the discovery of penicillin. So when Waksman decided to elaborate on that, he systematically screened soil bacteria, primarily streptomycetes, that he was working on for their ability to inhibit growth of bacteria. An extremely simple method and extremely powerful, he got a Nobel Prize both for the method and for the discovery of Streptomycin, the first antibiotic capable of treating tuberculosis. And then suddenly something happened in the early '70s. It looks like somebody turned off our ability to discover new compounds. The most effort resulted in rediscovery of things like penicillin and streptomycin. So then it became apparent that the soiled microorganisms that Waksman and others had been working on is a very limited resource, only about 1% of microorganisms from any external environment are going to grow in our Petri dishes. The rest are uncultured, so 99% of the enormous diversity on the planet are uncultured microorganisms. It's a fascinating paradox. So then looking back at our timeline, then there is a gap when nothing is happening, and then the last decade, a number of new compounds and classes have been introduced, so it looks like we are getting back in the game. That, however, is an illusion. If you replot this graph not by year of introduction of compound, but by year of discovery, what you will notice is that these new discoveries actually collapse back to the golden era, these are compounds that were discovered a long time ago, didn't seem very promising, and were dropped. And now, we are resuscitating them because we don't have anything better. So that is where we are.
Now, of course realizing that natural products kind of exhausted themselves, the industry decided to build a different platform for antibiotic discovery based on synthetic compounds, and of course, what helped was that Combinatorial Chemistry was producing an enormous variety of molecules. Genomics and Proteomics could give you new targets. High-throughput screening was developed. Rational design, and it all seemed ten years ago that the problem was going to be rapidly solved. So then the result of this very well thought through platform was closing of anti infectives divisions in the big Pharma. The platform did not work. And the reason that it didn't work, as we now realize is because synthetic compounds are literally running into a barrier. And this barrier is the elaborate multi-drug resistance pumps that bacteria carry, especially effective in gram negative bacteria. The first of trans-envelope pumps was actually discovered in my lab a number of years ago by O. Lomovskaya. So the pump interestingly recognizes molecules not based on geometry as most enzymes would, or transporters, but based on polarity. So anything that is hydrophobic will pick up and export out of the cell. And indeed, in order to cross the inner cytoplasmic membrane, compounds have to have some hydrophilicity. This is all drugs that have intracellular targets are like that, so then the pump is very ingenious design that will take anything that this hydrophobics, meaning any toxin or antibiotic and pump it out. Natural products have properties that evolve as it allows many of them to bypass the pump, we still do not understand very well what those properties are. There's an effort to understand that, but so far, we're not there yet.

Teixobactin kills pathogens without detectable resistance

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