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Infectious Diseases

New Antibiotics, Potential and (Nearly) Actual

Some antibiotic news today: first off, there’s a new multinational collaboration (CARB-X) to work on drug-resistant bacteria. Among other things, it’ll be giving grants to small companies in the US and Europe who are working in the area. They’re especially targeting new varieties of compounds, rather than variations on existing scaffolds, which I think is a good use of the money. It’s a public-private effort, with money coming in from the US HHS, the Wellcome Trust, and several other sources. This seems like a good idea, and it’s certainly addressing a real need, so I hope that something comes from it.

And in the odd antibiotic field, there’s this report in Nature. It’s been known for many decades that soil bacteria, since they’re in constant competition with each other, produce a variety of interesting antibiotics (in fact, many of the interesting antibiotics we have come from just that source). This hasn’t been observed much in the bacterial colonies that are present in all human bodies, but this latest paper has an example: lugdunin, a cyclic peptide thiazolidine derivative. It’s produced by Staphylococcus lugdunensis, and it’s one of the very few examples of such nonribosomally synthesized peptide natural products in human-associated bacteria.

It’s a pretty effective compound against S. aureus and a number of other gram-positive pathogens, including ones with resistance to common antibiotics. That goes for in vitro assays and in vivo ones (topical skin infection in mice). It’s clean against various human cell lines, though. Interestingly, serial passaging against the bacteria, which is a quick way to breed resistant strains, did not produce any against lugdunin. Its mode of action is unknown, although (like daptomycin) it seems to shut down a number of metabolic pathways at once. No one’s completely sure how daptomycin works, either – in general, it seems to be membrane disruption, but with specific details unknown. Lugdunin might be doing something similar, but that’s a topic for further research, which I think we can assume is underway or will be shortly.

The paper notes that a fair percentage (roughly a third) of adults have their nasal passages colonized by S. aureus, and that this correlates with the likelihood of nasal infection. There have been proposals to wipe out the pathogen from individual patients to save on trouble later on, but that isn’t easy. When this research team looked at 187 patients, they found a strong correlation between S. lugdunensis colonization (which was present in about 10% of the sample) and low incidence of S. aureus, which suggests that more people could possibly benefit by exposure to the former bacterium. In keeping with the lack of success at breeding resistant organisms, all of the clinically isolated S. aureus samples were still susceptible to lugdunin. So there are two public-health implications to this work: a potential new antibiotic, and a potential new microbiome tactic.

 

 

29 comments on “New Antibiotics, Potential and (Nearly) Actual”

  1. JSM says:

    Not so impressed with the activity – they didn’t quite achieve 3-log killing in the topical model, and barely a log in the deeper infection. Furthermore, there were completely unresponsive infections in the mice – though they didn’t identify resistant organisms in vitro after continuous passage, it’s possible in vivo conditions could have facilitated this process for these cases.

    As for the human carriage data, I would’ve liked to see validation that the strains they identified as lugdunensis actually carry this NRPS. And instead of a fancy mass-spec, some PCR would’ve done ^_^.

    I worry sometimes about this new antibiotic hype in the major journals (new antibiotics have been reported for decades in J Antibiotics. Lugdunin, teixobactin – the verdict is still out on whether these will pan out to anything at all.

    1. tangent says:

      Maybe the low activity is why they didn’t get resistance?

      Is there some reason to think that wild S. aureus and other skin biome might somehow only have recent exposure to lugdunin? Because if they do have long exposure, and they haven’t developed resistance mechanisms… I’m somewhat suspicious. We’ve got daptomycin-resistant S. aureus, why not lugdunin-resistant. To stereotype, you get your mileage with antibiotic natural products by picking them up from one environment and hitting naive species in another.

  2. bhip says:

    In related news, the first microbiome drug failed in cutting the risk of Clostridium difficile infection (CDI) in patients who had completed antibiotic treatment for CDI….
    http://www.fiercebiotech.com/biotech/seres-shares-crash-after-microbiome-drug-flunks-phii

  3. Barry says:

    if you look up Lugdunin in Wikipedia, you see a wrong structure represented. Their graphic is missing the sulfanylmethyl that is present in the IUPAC name (and in the molecular formula)

    1. Ed says:

      The chemical structure shown in Wikipedia matches what is reported in the Nature article. There is no sulfanylmethyl because there should be no sulfanylmethyl.

      1. Barry says:

        of course, the IUPAC name and the molecular formula and the molecular weight reported might be wrong (and the represented structure might or might not be wrong). But the represented structure doesn’t correspond to the IUPAC name

  4. Kent G. Budge says:

    Barry,

    Wikipedia? Wrong? Well, flabber my gast.

    1. Not 2001 anymore says:

      Wikipedia is better than large swaths of the literature, honestly.

  5. Gaear Grimsrud says:

    The Board of Carb-X will never notice. No chemists. Disappointed here. But give them a chance.

    Where’s Chemists House?

  6. Mike Robe says:

    Such thiazole molecules are rampant in the literature, and it takes considerable effort to get membrane perturbation agents through the clinic, PLUS- Gram positive agents are a dime a dozen. The world needs a drug against the nasty Gram negatives.

    But Carb-X I see is heavily staffed with Biologists and industry members who did not, as far as I can examine, even have their name on an recent clinically relevant antibiotic patent. I hope their grant reviewers have some chemistry experience. We know plasmids and resistance mechanisms exist now, so keep the funds out of this realm. Science has run out of chemicals to screen on this planet and it takes some ingenuity to find them now, let alone optimize them for human use. And anything discovered today might be available maybe in the year 2030- if you follow the fate of discovered antibiotics from chemical birth to PIII approval. That’s why I am surprised such chemical drug hunters are absent at Carb-X, they might actually help them succeed, and shorten the process. If not, I hope Carb-X is in for the long haul.

    1. Dr. Manhatten says:


      0
      In the pipeline
      Derek Lowe’s commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine.
      Derek Lowe
      By Derek Lowe

      New Antibiotics, Potential and (Nearly) Actual
      By Derek LoweJuly 29, 2016
      Some antibiotic news today: first off, there’s a new multinational collaboration (CARB-X) to work on drug-resistant bacteria. Among other things, it’ll be giving grants to small companies in the US and Europe who are working in the area. They’re especially targeting new varieties of compounds, rather than variations on existing scaffolds, which I think is a good use of the money. It’s a public-private effort, with money coming in from the US HHS, the Wellcome Trust, and several other sources. This seems like a good idea, and it’s certainly addressing a real need, so I hope that something comes from it.

      And in the odd antibiotic field, there’s this report in Nature. It’s been known for many decades that soil bacteria, since they’re in constant competition with each other, produce a variety of interesting antibiotics (in fact, many of the interesting antibiotics we have come from just that source). This hasn’t been observed much in the bacterial colonies that are present in all human bodies, but this latest paper has an example: lugdunin, a cyclic peptide thiazolidine derivative. It’s produced by Staphylococcus lugdunensis, and it’s one of the very few examples of such nonribosomally synthesized peptide natural products in human-associated bacteria.

      It’s a pretty effective compound against S. aureus and a number of other gram-positive pathogens, including ones with resistance to common antibiotics. That goes for in vitro assays and in vivo ones (topical skin infection in mice). It’s clean against various human cell lines, though. Interestingly, serial passaging against the bacteria, which is a quick way to breed resistant strains, did not produce any against lugdunin. Its mode of action is unknown, although (like daptomycin) it seems to shut down a number of metabolic pathways at once. No one’s completely sure how daptomycin works, either – in general, it seems to be membrane disruption, but with specific details unknown. Lugdunin might be doing something similar, but that’s a topic for further research, which I think we can assume is underway or will be shortly.

      The paper notes that a fair percentage (roughly a third) of adults have their nasal passages colonized by S. aureus, and that this correlates with the likelihood of nasal infection. There have been proposals to wipe out the pathogen from individual patients to save on trouble later on, but that isn’t easy. When this research team looked at 187 patients, they found a strong correlation between S. lugdunensis colonization (which was present in about 10% of the sample) and low incidence of S. aureus, which suggests that more people could possibly benefit by exposure to the former bacterium. In keeping with the lack of success at breeding resistant organisms, all of the clinically isolated S. aureus samples were still susceptible to lugdunin. So there are two public-health implications to this work: a potential new antibiotic, and a potential new microbiome tactic.

      7 comments on “New Antibiotics, Potential and (Nearly) Actual”

      JSM
      July 29, 2016 at 9:31 am
      Not so impressed with the activity – they didn’t quite achieve 3-log killing in the topical model, and barely a log in the deeper infection. Furthermore, there were completely unresponsive infections in the mice – though they didn’t identify resistant organisms in vitro after continuous passage, it’s possible in vivo conditions could have facilitated this process for these cases.

      As for the human carriage data, I would’ve liked to see validation that the strains they identified as lugdunensis actually carry this NRPS. And instead of a fancy mass-spec, some PCR would’ve done ^_^.

      I worry sometimes about this new antibiotic hype in the major journals (new antibiotics have been reported for decades in J Antibiotics. Lugdunin, teixobactin – the verdict is still out on whether these will pan out to anything at all.

      Reply
      bhip
      July 29, 2016 at 9:41 am
      In related news, the first microbiome drug failed in cutting the risk of Clostridium difficile infection (CDI) in patients who had completed antibiotic treatment for CDI….
      http://www.fiercebiotech.com/biotech/seres-shares-crash-after-microbiome-drug-flunks-phii

      Reply
      Barry
      July 29, 2016 at 9:52 am
      if you look up Lugdunin in Wikipedia, you see a wrong structure represented. Their graphic is missing the sulfanylmethyl that is present in the IUPAC name (and in the molecular formula)

      Reply
      Ed in reply to Barry
      July 29, 2016 at 10:44 am
      The chemical structure shown in Wikipedia matches what is reported in the Nature article. There is no sulfanylmethyl because there should be no sulfanylmethyl.

      Reply
      Kent G. Budge
      July 29, 2016 at 9:58 am
      Barry,

      Wikipedia? Wrong? Well, flabber my gast.

      Reply
      Gaear Grimsrud
      July 29, 2016 at 9:59 am
      The Board of Carb-X will never notice. No chemists. Disappointed here. But give them a chance.

      Where’s Chemists House?

      Reply
      Mike Robe
      July 29, 2016 at 10:14 am

      “But Carb-X I see is heavily staffed with Biologists and industry members who did not, as far as I can examine, even have their name on an recent clinically relevant antibiotic patent. I hope their grant reviewers have some chemistry experience.”

      I am a (micro)biologist and worked in antibiotic R&D for 30 years. And yes, I absolutely agree with you that medicinal chemists are essential to their success. I have the deepest respect for the many fine med chemists I have worked with over the years, and I learned an enormous amount from them. As well, my colleagues in DMPK and toxicology were critical to our teams.
      For success, you need all of these individuals advising on potential development programs.

      “The world needs a drug against the nasty Gram negatives.” Wholeheartedly agree with you on that one as well! For MRSA, you have vancomycin, daptomycin (Cubicin), linezolid (Zyvox), ceftaroline and several new glycopeptides.

  7. SlimtoNone says:

    Mike Robe is right. Been wondering about the cockeyed funding of antibiotic chemistry for quite some time- its skewed towards biology. Then what happens is the biology stalls and the chemistry is the first to get cut. Sure it makes developers happy, the high priced consultants like the guy writing clinical happenings at The Perfect Storm- but they do nothing to discover new chemical matter. With all the brains in this area in Boston alone you’d think chemistry would be highlighted. Where’s the teixobactin fellow? Where’s those guys struggling for years working on the tetracyclines, or the macrolides? Those are the guys that need to be involved. Not only for their sage advice but so they can keep the charlatans at bay with 50 million in Antibiotic Bucks floating around. Without chemists you might as well shred the money.

  8. JeffC says:

    Ok let’s clear this up. Carb-X board will heavily rely on Wellcome Trust for the review part to make sure they pic decent projects. They have a pretty extensive group of industry experience med chemists to talk to. Wellcome has a pretty excellent track record in antibiotics and picking the right projects to develop. Last time I checked they funded a bunch of academics and lots of companies. In fact you can find Wellcome money in the background of much of the current antibacterial pipeline. Achaogen (Phase3) is the most advanced but there are loads more (Antabio, Venatorx etc etc) and they are almost all small molecules so the med chem resource there is pretty decent. Oh and Tim Jinks is actually a chemist so the Board does(!) have a chemist. Whatever you think of this, there a real shortage of capital in the early stages of product development in this field and the main players in this (BARDA and Wellcome) have a pretty good track record in this field. They’ve been putting cash in for more than a decade while everyone else exited the field so maybe they might have more expertise than you think. I don’t see anybody else putting their hands up with hard cash. While some companies have stayed committed to this, I don’t see many of the bigger companies rushing to help.

  9. Barry says:

    ah. The Wikipedia entry has been fixed. They kept the structure (as per the Nature paper) and made the IUPAC name, the molecular formula, and the mol. weight conform

    1. anon says:

      That is the real value of Wikipedia. It is constantly curated and corrected in a way that the primary scientific literature never can be.

      From what I can tell by looking at the history of the Wikipedia article, the original incorrect structure information was taken from ChemSpider. This should give pause to anyone who believes that professionally curated chemical databases are inherently more reliable than a volunteer effort such as Wikipedia.

      The incorrect ChemSpider entry has been deprecated now, I suspect in part because ChemSpider staff interact with Wikipedia and its chemistry editors.

  10. gippgig says:

    While thiazoles are quite common, the fully reduced ring in lugdunin isn’t. Note that this ring spontaneously epimerizes so lugdunin is a mix of diasteromers.

  11. lynn says:

    It’s nice that CARB-X is trying this – but I too am worried about the people they will be asking to review projects. It has to be chemists, biologists, and toxicologists with real industrial experience in the field. And I would bet that they will find very very few compounds that are developable. When the European IMI project ENABLE set out to establish a “factory” for taking hits to candidates, it was easy to organize the optimization end of the consortium – but finding hits to advance to leads has been largely a bust. It’s been said here many times, Big Pharma had hundreds if not thousands of scientists – yes chemists as well as biologists, working nicely together – with incredibly low novel [clinical] output in the antibacterial area. This was discussed in the Pew Roadmap for antibacterial discovery [reported here in May] which tried to lay out the basic science needs in the area that will be needed to further new discovery. I believe CARB-X will also foster discovery/development of diagnostics…and since that’s pretty much doable, that’s where the effort will end up. Good luck to the small companies – there are some which might make some progress with some monetary help. But new classes of small molecule antibacterials will still be hard to come by [unless there are, eventually, some useful antibacterial peptides that are systemically safe and active]. This is a tough problem.

    1. bradpalm1 says:

      Lynn…as you know we’re such a small company trying to pursue novel antibiotic drug development for the last several years using innovative metal coordination chemistry, but we continue to run up against funding and sponsorship roadblocks which force us to shelve very promising projects for lack of vision and support by the same entities who decry the lack of invention in this space. Hopefully this latest collection of reviewers at CARB-X will remain true to supposed mission of this “public-private initiative” and actually help pre-clinical companies such as ourselves translate an innovative concept into an actual novel antibiotic ready for simple testing. Who knows? It may actually work.

    2. anonao says:

      “but finding hits to advance to leads has been largely a bust”
      Source?

  12. Barry says:

    Membrane disrupters have the advantage–since they don’t have to act in the cytosol–of not being subject to the efflux pumps that defeat many novel antiinfective candidates. But if their action depends on aggregation (like e.g. amphotericin B) they may fail a Shoichet test for lead-likeness.
    Antibiotic discovery is a hard problem that won’t be made easier by excluding Med. Chemists

    1. milkshake says:

      it does look like a membrane pore opening molecule – the aminoacid residues are all valine, leucine, one Trp. Alternating D and L aminoacids to make it rigid and stable to enzymatic hydrolysis. I think this one acts like a greasy stiff donut with a polar hole at the center

      1. Barry says:

        if indeed it is putting a leak into the bacterial membrane (“I’ve got a hole in me pocket!”) it wouldn’t be subject to any of the known resistance mechanisms. But I’d worry about how well it discriminates bacterial membranes from mammalian membranes. Amphotericin B (which punches holes in fungal membranes) has notorious tox. issues, despite a bias towards integrating in membranes that contain ergosterol (that mammalian membranes lack)

        1. tangent says:

          Though fair to say fungal membranes are harder to discriminate from ours than bacterial are in general? Gram-positive wall in particular is a *relatively* juicy target. (not to trivialize the drugs against them!)

          It seems like we have more marketed drugs that block Gram-positive wall synthesis (vancomycin, various -vancins, teicoplanin) than that disrupt them (daptomycin, ?) without disrupting everything (gramicidin and so on) so having another like daptomycin would be nice.

  13. JJJ says:

    Could anyone tell how Aspergillomarasmine A is doing now ? I found in Nature not long ago it was a potential powerful beta lactamase inhibitor. Thanks.

    1. NJ BugHunter says:

      It was reported as an NDM-1 inhibitor, does not inhibit serine beta lactamases. Acts by sequestering Zn++ which is not a very promising mechanism.

  14. gippgig says:

    The main mechanism of amphotericin is extraction of sterols from the cell membrane rather than pore formation (which is not required for activity). See Nature Chemical Biology 10 400, doi: 10.1038/nchembio.1496

  15. drsnowboard says:

    To reiterate what JeffC says above, The Wellcome Trust definitely does involve medicinal chemists in the funding, performance review and re-funding of small molecule projects (disclaimer: I am one) . Given its primary driver of ‘unmet medical need’ it has been substantially funding antibiotic research and other ‘neglected’ areas for some time.
    It is much less susceptible to the biology founded “Look , it does this!!” funding pitch than some seem to believe. If you believe the previous medchem industry teams ‘failed’ in low output of NCE for infection then trying the Broad Institute as medchem source is not a giant leap , but I agree having some wizened old cynics in the room can only help.

  16. wlm says:

    Personally, I am suspicious of using human- or human microbiome-derived antimicrobials, whether small molecules or peptides, as therapeutics. I think that encouraging the development of resistance to something we are already using is unwise and might have unforeseen consequences.

  17. jeff says:

    good

Comments are closed.