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A New Antibiotic Class, Which You Don’t Get to Say Very Often

Never say never. Screening natural product extracts for new antibiotics has been a diminishing-returns exercise for quite a while now, which is too bad, since basically every single important antibiotic class came via that route originally. Bacteria compete with each other (as do plenty of other organisms), and seeing what they’ve come up with after a billion years or so of infighting has been very productive.

But when you run such screens now, you tend to find things that we’ve already found – either the exact compounds, or as close as makes no difference. (That’s as opposed to random screening of compound collections, when you tend to find those and a bunch of things that are nonselectively toxic, which does you no good, either). Digging your way through the pile of unusable hits is a challenge, and there’s no guarantee that there will be anything left after you do.

So I’m particularly surprised and impressed by this new paper (press release here, C&E News article here), which reports the discovery of a new variety of antibiotic entirely, and by good old soil-sample screening, at that. (Update: here’s the full paper). It’s a collaboration between several research groups in Milan and a group at the Waksman Institute at Rutgers, whose namesake would be glad to hear the news. The compound is pseudouridimycin, a nucleoside analog that inhibits bacterial RNA polymerase. That’s the same target as rifampicin, but this molecule binds (according to an X-ray structure) to a slightly different region of the protein, and is in fact additive with it when co-administered. Finding a compound that is such a good inhibitor of bacterial RNAP without activity at the human enzyme is another welcome surprise.

It’s an active-site mimic of UTP, uridine triphosphate, which is not an easy feat. Phosphates are, of course, extremely important in biochemistry, but making small molecules that bind to their recognition sites is difficult. Look, for example, at the wide world of kinase inhibitors – out of all the compounds described in that area, only a tiny fraction seem to avail themselves of the phosphate-binding region of the proteins. The same goes for many other classes (phosphatases, naturally, as well as helicase inhibitors, etc.) It’s the concentration of negative charges, surely. The protein binding sites are (naturally enough) very polar in the opposite direction, and don’t seem to care much about the kinds of molecules that normally populate screening collections. But at the same time, they’re quite picky and directional, so just throwing a bunch of polar stuff at them indiscriminately doesn’t get you anywhere, either.

But pseudouridimycin manages it. Coming off a 6-amino pseudouridine core is a glutamine-glycine chain, with the glycine being N-hydroxylated at one end and functionalized with an N-formamidine at the other. Binding to the nucleoside triphosphate site makes it harder for the enzyme to mutate its way out of trouble, and indeed, development of resistance in culture seems about ten times slower for this compound than is does for rifampicin, which is good news. It’s active against drug-resistant stains of mycobacteria, which is something that we could very much use, considering the foul strains of tuberculosis that are at large.

This looks like a promising drug candidate all by itself, and I hope that discovery of this structural class will lead to interesting analogs as well. Past that, I wonder if that whole modified peptide side chain can be repurposed to hit triphosphate binding sites in general – I don’t think that will be easy, but considering how hard it is to make headway in that area, I think it’s probably worth a shot. . .

17 comments on “A New Antibiotic Class, Which You Don’t Get to Say Very Often”

  1. Barry says:

    A structurally new antibiotic is exciting; in this case, the binding mode (if not the target) is novel, too. That phosphate pocket has at least two demerits for a med. chemist. First is the huge hydration burden of small molecules as polar as this. That makes it unlikely to get passively through phospholipid bilayers to the target tissue (even out of the gut if given orally)The phospholipid bilayer was invented a couple of billion years ago to compartmentalize just such hydrophilic things. Simultaneously, the cost of stripping off those waters has to be paid every time such a drug candidate binds to its target; such polar contacts are highly directional and can confer selectivity to binding, but rarely gives much net enthalpic binding.
    Outside the paywall, I can’t see what they mean by “potent”.

    1. KevinH says:

      Outside the paywall, I can’t see what they mean by “potent”.

      IC50 for inhibiting bacterial RNAP is 0.1 uM. IC50 for in vitro antibacterial is between 2 and 16 uM, depending on the strain. (And their screen included some multiple-drug-resistant Staph.) IV in mouse the ED50 was 9 mg/kg in a Strep peritonitis model.

    2. Chris Phoenix says:

      For most drugs, I’d think it was a negative if they were difficult to administer. For an antibiotic, maybe it means it won’t be fed to animals routinely and overprescribed to humans quite so much, so it’ll take longer for resistance genes to build up in the wild.

    3. Morten G says:

      I think it might piggy-back on scavaging transporters for nucleosides or nucleotides. Active transport baby!

  2. Chrispy says:

    The compound has a top potency of 2uM, which is a bit disappointing. The paper is remarkably thorough, though, and includes RNA polymerase mutants, crystal structures, animal data, and the generation of a half a dozen (less potent) analogues. Nice work.

    I have institutional access, yet the paper was easier/faster for me to find on SciHub by searching the title.

  3. Design Monkey says:

    Weelll, sorta seeing more than average hydroxylamines and hydroxamic acids lately. Various Zn binders, that’s a matter of course, but in antibiotics too.

  4. gippgig says:

    Why not show the structure?
    The article is available at: biorxiv.org/content/early/2017/02/08/106906
    It’s not that selective; it inhibits human RPO2 at 1/7/>20μM vs. .1/2/8 for E. coli (figures for different UTP levels).

  5. Anon says:

    Gram negative potential?

    1. Vaudaux says:

      The natural product is active vs wimpy gram-negatives like Haemophilus influenzae and Moraxella catarrrhalis (which is also true of rifampin). If they had measurable activity vs E coli or P aeruginosa, they would surely have said so. Potency vs the isolated enzyme was the same vs both E coli and B subtilis enzyme, so presumably the issue is failure to accumulate in the cytoplasm of serious gram-negatives. Would be nice if they had tested efflux-deficient mutants or bugs with permeabilized outer membranes.

      (The manuscript version of the paper is free via biorxiv, as gippgig said)

      1. Anon says:

        Good point; how could this NP lead be optimized in to a useful drug for gram-negative?

  6. Derek Lowe is my bitch says:

    Hey yo Lowe, when we gonna get our drugs mayn?

    1. ChemGod says:

      Well you’re gonna have to be a little patient for that sonny

  7. aairfccha says:

    “basically every single important antibiotic class came via that route [natural product screening] originally.”

    Sulfonamide?

    1. TB says:

      Incorrect. fluoroquinolones, sulfonamides, oxazolidinones, nitroimidazoles, and the anti tubercular agents isoniazid, ethambutol, pyrazinamide, and bedaquiline to name just a few were designed by chemists and are synthetic in origin.

      1. Morten G says:

        Arsphenamine.

        And Derek, please, we’re not all superchemists. Please include structures in your posts.

      2. Derek Lowe says:

        This will make a good follow-up blog post, actually. . .

  8. tangent says:

    Did these folks do anything unusual in their soil screening, that could be repeatable, or does it seem like they just got lucky?

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