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Chemical Biology

A New Antibiotic Candidate

Antibiotic discovery is always welcome. Here’s a new one from a well-searched area (Actinomycetes extracts), and the authors (university teams from McMaster, Indiana, and Montreal) did a lot of groundwork to make sure that they weren’t just going to rediscover known agents. That’s a serious problem with broad-based antibiotic screening, as you’d imagine, and there are several ways to try to get around it. One is to engineer the organisms being screened – you can try them with and without various resistance mechanisms to see where you stand. But in this case, the search concentrated on wild-type Actinomycetes that showed unusual biosynthetic gene clusters by sequencing. A phylogenetic tree was constructed for these (various non-ribosomal protein synthesis genes) and the search was biased towards the least-homologous ones and the ones that showed the least similarity in known self-resistance genes. That latter part should, in theory, send you more often to the natural products that have new modes of action, as opposed to minor variations on known themes. If you’ve ever wondered how bacteria manage not to kill themselves with their own antibiotics, that’s a big part of the answer: they have their own resistance mechanisms already in the can – often several of them, and their genes tend to be clustered with the biosynthesis genes for the natural product and regulated simultaneously.

This approach led to “corbomycin”, shown at right. It’s broadly similar to the known peptidoglycan antibiotics such as complestatin and chloropeptin I but with some extra ring closures, giving it quite a structure. These agents are known to be mostly active against gram-positive organisms, but they maintain this activity even against vancomycin-resistant strains, which makes their mechanism of action of interest. There have been some proposals in the past, but this work identifies that actual MOA as binding to peptidoglycan and thus inhibit a range of autolysin activity, which inhibits cell wall synthesis. Inhibiting any single autolysin enzyme would probably be a losing strategy, since there’s a lot of redundant activity in that area, so the bind-to-the-natural-substrate mechanism is a better way to go and should (as in the case of vancomycin) lead to slower development of resistance.

The paper demonstrates topical activity in a mouse model. It’s unknown what might happen when you try to dose corbomycin systemically, although you’d have to figure that some significant formulations work might be involved, since that’s not a very soluble-looking compound. But I’m glad to see it and also glad to see the mechanism of this whole class illuminated. Now what we need is something like this that messes with the gram-negatives, too!

23 comments on “A New Antibiotic Candidate”

  1. Barry says:

    Binding to peptidoglycan is exciting. It means that corbomycin doesn’t need access to the bacterial cytosol and can’t be defeated by a efflux pump

  2. no body says:

    I disagree with you Derek, this one looks quite soluble!

    1. Barry says:

      crystallinity is hard to predict, but this one seems unlikely to stack neatly into a brick. If I were trying to predict liabilities, I’d worry that it will suffer rapid renal clearance. But if you’re the last line of defense against a Vancomycin-resistant organism, continuous infusion can work

    2. An Old Chemist says:

      This compound with free -COOH and many phenolic -OH groups will certainly be very soluble only at basic pH, say at ca. pH=9.0-11.00.

      1. Derek Lowe says:

        That was my impression, too. God only knows what its crystalline state is like, but one could imagine a lot of pretty good hydrogen bonds in the solid phase, and breaking those up to get into solution will exact a cost. . .

        1. Troll Toll says:

          You gotta pay the troll toll to get into the solute hole

          1. ManOfCulture says:

            A true man of culture — an appreciation for cutting edge chemistry mixed with It’s Always Sunny. I applaud you.

      2. w says:

        pH 8.5 50% AcN/H2O

  3. steve says:

    The problem is that there is no market for new antibiotics. Several companies with new, effective antibiotics have recently crashed and burned because docs save new antibiotics as a last resort. Further, all antibiotic manufacturing has moved to China leaving the US vulnerable in the face of a national emergency. There needs to be a national effort to subsidize US antibiotic development and marketing or else we will face a real crises.

    1. loupgarous says:

      Agreed. Our national security depends even more on our ability to treat new, resistant strains of bacteria than it does on our nuclear arsenal, which we are about to spend billions on as we revive “flexible response” with low-kiloton nukes (for a proportional response to Russian weapons in the same low yield range).

      Since Russia’s spent effort and money on developing antibiotic resistant strains of plague and anthrax over a period of decades, what Steve proposes shouldn’t even be a hard sell. If Big Pharma can’t or won’t develop and manufacture antibiotics less prone to bacterial resistance for the free market, then make them as we do nuclear explosives – on contract to the Federal government (both DHS or DoD already stockpile medications against national health emergencies, and CDC already distributes drugs that aren’t profitable, but are life-saving.).

      The challenge would be to avoid treating this like a new weapon system. Lockheed Martin could burn a billion on this without delivering anything but a stack of excuses for cost overruns.

      1. Matthew TKK says:

        Wouldn’t govt-developed novel antibiotics capable of neutralising those threats be quite likely to be kept secret, to remove Russia’s apparent need to develop such bioweapons further?

        1. Barry says:

          What’s kept secret isn’t approvable by the FDA

        2. loupgarous says:

          No more than the new acetylcholinesterase reactivator oxime drugs have been declared secret, even though some show promise of being active against Russia’s novichok nerve agents, which inhibit AChE in ways not treatable with the older oxime drugs such as pralidoxime.

          I hope someone with the defense and homeland security research outfits has been looking at the newer oxime AChE reactivators, as well as galantamine, which works synergistically with the militarily significant oxime reactivators to protect AChE in rats exposed to VX (another nerve agent whose toxicity isn’t as treatable with pralidoxime as, say, sarin’s is).

        3. loupgarous says:

          “Wouldn’t govt-developed novel antibiotics capable of neutralising those threats be quite likely to be kept secret, to remove Russia’s apparent need to develop such bioweapons further?

          Russia needs to comply with the Chemical Weapons Convention and the Biological Weapons Convention (of which it was not just a signatory, but a depository state). When Russia was the dominant country in the USSR, it was secretly breaking the BWC before Brezhnev’s signature had dried on the treaty and kept doing so until two of Biopreparat’s deputy directors defected to the West in 1992. Russia was an original signer on the CWC, yet we know they possess and USE novichok nerve agents specifically banned by the CWC.
          It doesn’t matter what antibiotics we have on the shelves, or whether Russia’s just going to work strains of their current bioweapons up to be resistant to them. We should do what we can to develop new antibiotics to which our currently resistant pathogens haven’t evolved to be resistant. Compared to natural evolution and resistance plasmid transfer, the biological weapons community are rank amateurs.

    2. VCinDC says:

      Thats because the public expects cheap antibiotics, and if they were priced like Spinraza there would be 47 companies looking at antibiotics instead of orphan diseases.

      The other issue in the antibiotic field is that the execs propped up in these companies don’t understand the field, and if they do, aren’t telling anyone how difficult it is to create a new antibiotic from scratch or they overstate their efficacy leading to class action suits and SEC issues. Overpaid execs with no clinical development experience have doomed antibiotic and regular discovery companies alike, so no surprise there.

      But look at the antibiotic company Paratek Pharmaceuticals of Boston. They had 2 drugs approved, both orally active and recently had BARDA commit to 285M$ to stockpile Omadacycline for anthrax attacks. This small but well-funded company developed the drug from scratch, had to struggle to get it to approval, and the chemists won the ACS Heroes of Chemistry award for 2 approvals the same day. Success is possible but you better be in it for the long haul like they were. Just discovering an antibiotic that works isn’t enough- you have to a long-term plan, and Pharma doesn’t have that patience anymore.

      1. ananamouse says:

        Paratek was in C and E news lately, last June. They didn’t go to China and don’t rely on them for sourcing, going to Portugal and a Swiss API manufacturer followed by Ireland.

        One of the few companies in the US to do so, without selling out for lower cost drugs.

    3. alex says:

      The NHS is trialing subscription-style payments for antibiotics, which could have some interesting (and hopefully positive) consequences on the economic realities of developing and selling novel antibiotics.

  4. cynical1 says:

    A new mechanism of action is always nice to see but I think I would like to see a side by side comparisons of MICs of corbomycin with televancin and linezolid against a panel of gram positive bacterias. (Vancomycin is no longer the gold standard of any sort.)

  5. Barry says:

    The Free Market will never pay for development of a novel antibiotic that requires continuous infusion (as this one might). But an infusion-only drug would also be unattractive to the pirate industry; it might be spared the irresponsible wide distribution that cultivates resistance in pathogens.
    And those H-bonds can be satisfied by solvent, as well as by stacking; there may be little or no cost to dissolution

  6. navarro says:

    over christmas break this past year i nearly died from sepsis. when i first went into the hospital they treated my infection aggressively while awaiting cultures to find out exactly what they were dealing with. i.v. vancomycin, daptomycin, and a couple of others my 104.5 fever obscured. i found out how much i lucked out when the cultures came back and while it was a staph infection, it was a nonresistant strain. 5 weeks of daptomycin wiped it out and i was able to do most of my recovery from the infection at home. i’m still recovering mobility from the damage the infection caused in my knee. 3 days a week of out-patient physical therapy, a lot of opioids for pain, and i may get released back to work by the end of march.

    as i said, i was lucky. someone with a multiply resistant strain might well be in the hospital still if they even survived. new antibiotics with novel modes of action are absolutely needed if we aren’t to return to those days when an infection was a death sentence.

  7. ScientistSailor says:

    If anyone is interested in the economics of the abx market, take a look at this series of videos by some experts in the field.

    Tl;DR: If you are handed an approved antibiotic for free, you are still negative $400 million over the first 5 years on the market.

  8. An Old Chemist says:

    This may be an aside, but I lost a really lot of money in investing in the Tetraphase pharmaceuticals stock (TTPH). I believed that Andy Myers versatile synthesis of tetracyclin analogs will certainly find a few analogs with activity for many kinds of bacterial infections. But, instead, I saw the stock tumble from high 40s to below one dollar as it went through a reverse split of 20-to-1. Now, I would rather invest in oncology biotechs for big returns!

  9. Dr. Manhattan says:

    For small antibiotic companies that need to get from hit to lead to candidate, one funding source is Carb-X, run out of Boston University and dedicated solely to funding new infectious disease products (primarily antibiotics). The funding is competitive with a good program having a decent chance of getting funding and there is no payback to Carb-X. You can go to the Carb-X web site to see the companies and their programs. Unfortunately it does not solve the longer term problem of the financial outlook for antibiotic companies.

    A novel antibiotic that is effective against MDR strains will be most likely “put on the shelf” for use against really tough infections. Makes perfect sense from a medical standpoint but doesn’t work as a sustainable model for antibiotic companies. There are some groups giving serious thought as to how to build a financially sustainable model fro antibiotic R&D.

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