A team from Northeastern University/Bonn/Novobiotic (and Selcia) has published a very worthwhile paper in Nature on a new antibiotic, with a new mechanism of action, via a new discovery technology. The compound itself is not the world-changing new last line of defense that everyone’s hoping for, but it’s nothing to sneeze at, either. And the platform used to find it is worth keeping an eye on.

A lot of people have had similar ideas to this one, based on the fact that the overwhelming majority of bacteria in any given environmental sample can’t be readily cultured. These organisms may well be able to produce useful antibiotics and other natural products, but how will you ever be able to tell if you can’t fish any of them out? In this work, Kim Lewis and Slava Epstein at Northeastern came up with a gizmo (the “iChip”, a name that you’d think would have been taken several times by now), that tries to get around this problem. After taking a soil sample and diluting it into media, you dispense aliquots into the wells of this chip. Then the chip is placed back into the soil, in the same place the sample was taken from, where semipermeable membranes allow environmental factors (whatever they may be) to diffuse across. This gives, apparently, a much higher culture success rate.

Using this on a soil sample from Maine and leaving the chip in situ for a month, a number of colonies formed. These were tested for their ability to grow outside the device in fermentation broth, and extracts of these were tested against pre-grown lawns of an S. aureus strain to look for useful antibiotic activity. Lo and behold, one extract cleared out a large spot – it turned out to come from a newly described bacterium (Eleftheria terrae, provisionally). The compound present has been named teixobactin, and here it is.

Purification of the active broth extracts showed increasing amounts of a compound with MW 1242 by LC/MS. Isolation of this substance (after clearing out the endotoxin that came along with it) allowed a good deal of NMR spectral assignment work, and coupling this with the identification of the biosynthetic gene cluster and degradation/derivitization analysis (advanced Marfey’s method) has allowed the structure to be assigned. It’s a pretty chewy one, with two rare amino acids and four D-amino acids. That would account, you’d think, for its properties: teixobactin has reasonable microsomal stability and shows useful PK after an i.v. dose in mice. (The authors also checked it for hERG, CYP inhibition, and plasma protein binding – the sort of thorough med-chem workup that you’d like to see more often, honestly).

And let’s pause a moment to reflect on the world we live in these days. This new bacterium’s genome was totally sequenced, as a matter of course, because we have the tools to do that without a second thought. Not all that long ago, just figuring out what this organism might be related to would have been a whole project of its own. Its biosynthetic pathway was thus laid bare, and our accumulated knowledge of nonribosomal peptide synthetase proteins made clear how this compound is produced, which is another thing that would have taken a big chunk of someone’s life in the old days. And then modern LC/MS and NMR techniques made comparatively short work of the structure, and any organic chemist should realize what that would have been like. Had anyone stumbled on teixobactin in the 1950s, back in the golden age of antibiotic discovery, they could have easily spent their career on it.

So how useful is the compound? It’s active only against gram-positive organisms, which is too bad, because we could really use some new gram-negative killers (their cell membranes make them a tougher breed). But the mechanism of action turns out to be interesting: studies of S. aureus with labeled precursors showed that teixobactin is a peptidoglycan synthesis inhibitor, but extended exposure and passaging did not yield any resistant strains. That’s close to impossible if an antibiotic is binding a particular protein target – stepping on the selection pressure will usually turn up something that evades the drug. When you don’t see that, it’s often because there’s some nonspecific non-protein-targeted mechanism, which can be problematic, but teixobactin isn’t toxic to eukaryotic cells in culture (and has a favorable tox profile in mice as well). It turns out that it binds to some of the peptidoglycan precursors, lipid II and lipid III. Vancomycin has a similar mechanism (binding to lipid II), but teixobactin has a wider spectrum of activity against lipid II variants (and lipid III as well). This mechanism makes developing resistance not so straightforward – the selection pressure is more of a bounce shot than a direct hit.

So overall, I’d say that the compound could be a promising alternative to vancomycin, and that’s no bad thing. There are vancomycin-resistant strains of S. aureus out there, and if you get infected by one, you’re going to need all the help you can get. I would assume that Novobiotic is working on the development, and I hope it goes well. There are plenty of challenges ahead (a reproducible scale-up fermentation being one that comes immediately to mind), but the compound has a good preclinical start on things. Teixobactin itself is not going to save the world from the oncoming problem of bacterial resistance, but it represents a promising line of attack.

This idea of going after cryptic bacterial strains has been around for a long time, but getting it to work has been another thing entirely. This is the most solid example that I’m aware of, and I hope that it’s just the opening of a new platform for antibiotic drug discovery. The traditional search for natural product antibiotics has pretty well come to a shuddering halt over the years – no matter how much effort you put into increasingly exotic soil samples and the like, you keep finding the same things (if you find anything at all). Unculturable organisms are the new frontier, and it’s safe to say that the iChip is going to be nowhere near the last word in exploring it. And at the same time, you have outfits like Warp Drive Bio trying to get organisms to express unusual compounds that aren’t normally seen, so the hope is that there are a lot of useful things out there that that we have never heard of.

As an aside, if you’re outside the field, you might wonder why it’s worth working so hard to find natural products when we have so many synthetic organic chemists in the world cranking out new compounds. One big reason is the ridiculous, insane hugeness of chemical space: the number of possible compounds at or under the molecular weight of teixobactin defies description, and I mean that in a completely literal sense. There are not enough resources on Earth, or in our entire solar system, to do enough organic synthesis to make any noticeable dent in that array. The idea of having compounds that bind to things like Lipid II is a good one, but they’re going to have to be large compounds, and exploring that space is daunting.

And then there’s the evolutionary factor. Bacteria are out there elbowing each other for space and nutrients every minute of the day, and they’ve been doing it for billions of years. They’ve had the time and motivation to come up with molecules that work to kill off their rivals, and we should take advantage of that legacy as much as we can. These molecules have not only had rigorous real-world tests of their mechanisms of action, they’ve also (perforce) had their properties optimized against their target organisms as well. Believe it, most large peptidic-looking things like teixobactin would have awful stability and pharmacokinetics as drugs. Finding the ones that don’t is nontrivial indeed.

Leave a Reply

Your email address will not be published. Required fields are marked *

You May Also Like