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Infectious Diseases

A New Bacteria-Killing Combination

I know that antiviral news is all the thing these days (post coming on that tomorrow), but there’s some encouraging antibacterial news as well, which we could always use. This paper reports progress in the cationic antimicrobial peptide (AMP) area. That’s been a field of interest for a long time, but it’s been tough. Update: here’s a new review of the area. There are a lot of organisms (lower and higher) that produce such agents, but they’re generally (1) not all that stable, particularly in the ways that we would like to administer them, and (2) need pretty high concentrations to be directly antimicrobial. They work by various membrane-disrupting mechanisms, and bacteria (particularly Gram-negative ones) have been seeing that sort of assault for a long, long time now and are accordingly well-prepared.

This latest work (from a large multicenter team headquartered in Singapore) is addressing another strategy, lower amounts of AMPs in synergy with other antibiotics. The idea is that you could affect the bacterial membranes enough to permeabilize them for antibiotic entry, even if you haven’t permeabilized them enough to kill the bacteria outright by just that mechanism. People have tried this before, too, and these attempts have been largely defeated by the other big membrane weapon that bacteria have: efflux pumps. Doesn’t matter that much if your antibiotic wonder drug gets past the membrane if it just gets spewed right back out, and that goes double for Gram-negatives, who have a double-walled membrane structure full of efflux machinery. Forget getting into the cytoplasm; you often can’t even keep your drugs in the periplasmic space between the inner and outer membrane thanks to the pumps kicking in.

But in this case they have an artificial polymer of poly-amidosaccharide and a poly-dimethyl-beta-lactam that gives a cationic species built up of beta-peptide linkages. That makes it more metabolically robust, but the really good part is that this material both seems to permeabilize the bacterial membrane and inhibit efflux. And it has no effect on mammalian cell membranes. In combination, Gram-negative species get killed by antibiotics (such as rifampicin) that normally they aren’t susceptible to (rifampicin being notoriously unable to penetrate most Gram-negatives).

This is shown both in vitro and in vivo, in mouse infection models, and it should be noted that infectious disease is one of the areas with the cleanest translation from small-animal models to human. Mice infected with nasty drug-resistant strains of E. coli, P. aeruginosa, and A. baumannii showed very strong responses to the combination of the polymer and rifampicin, while each agent by itself was completely ineffective. This combination idea even worked with novobiocin, which is almost never any good against most Gram-negatives unless you work up an efflux-crippled strain in the lab. Watching good ol’ novobiocin protect mice against a lethal challenge of A. baumannii (as is shown in this work) is quite something – normally, it would be about as effective in that situation as eating a handful of popcorn.

There are other groups working on similar principles of trying to synergize AMPs and (otherwise ineffective) antibiotics, but this is one of the best I’ve seen. Overall, the idea of using unnatural-ish peptidomimetic species on the AMP side of the combination makes a lot of sense, and I’m glad to see this sort of work delivering some results. We’re going to need them!

 

19 comments on “A New Bacteria-Killing Combination”

  1. Ted says:

    It occurs to me that we spent all of those ‘combichem’ years in the ’90s with the correct phrase tied to the wrong strategy…

    -t

  2. ScientistSailor says:

    Lots of poly-cationic things that work in a short-term mouse models fail immediately in further study due to renal toxicity. There are some hints in this work that these compounds might be safer, but they need to use the guinea pig model, mice aren’t sensitive enough.

    I won’t hold my breath…

  3. gigapig says:

    I’ve been taking low dose of penicillin to help ward off COVID. So far so good!

    1. Scientistsailor says:

      That’s not funny…

    2. IIPA says:

      I’ve been drinking beer, not so much to ward off COVID, but because I like beer. So far so good!

      1. Mad Chemist says:

        Yup, same here.

    3. Ganjun Yuan says:

      I think you do a good job! Because it is good for promoting your immune system to prevent COVID 2019 infection.

  4. hype says:

    The MIC values of these polymers are high.

  5. Zee Bendelstein says:

    Do we have a pathway though to economically develop such a combination and get appropriately remunerated for it though?

  6. Zee Bendelstein says:

    Trouble is: do we have a viable commercial path for those who foot the bill to develop this to get adequately remunerated for their troubles?
    For a dispassionate venture/biotech investor thinking about returns on their investment, antibiotics have proven a troublesome path recently.

    1. loupgarous says:

      Risk is unavoidable in investment, and especially in an industry where new products (where venture capitalists come into play) fail in late-stage development (mostly trials) 9/10 times.

      Even VCs who study Big Pharma problems to reduce risk (or to quote one of them, increase odds of success to “unity”) mainly succeed in attracting buyers for new drug candidates they finance before clinical testing, so the billions go to them, not to the drug companies who buy what the VCs invested in.

      You’re right, the expensive, hair-pulling part of drug development costs a ton. However, we have laws intended to compensate people to do safety and efficacy studies on orphan drugs and drugs grandfathered into the marketplace. Martin Shkreli led a phalanx of folks gaming that system to buy marketing rights to and re-study old drugs which are known to work and not notably toxic, and fleeced insurance companies, their policy holders, and those without enough health insurance out of millions.

      We may have to consider having Congress pay CROs (through the FDA) to do those safety and efficacy studies on drugs we need, but can’t find funding to develop, then license those drugs that their CROs find work to the drug industry (for a reasonable fee).

      Done correctly, that should provide safety and efficacy studies for new drugs like antibiotics the country needs, while not being something companies and their investors can game to drive the price of old, grandfathered drugs up for no good reason.

      1. ScientistSailor says:

        “Troublesome” is putting it mildly…

    2. eub says:

      This is ultimately a low-level question. The high-level question is: have we structured our rule set such that human health and welfare is promoted?

  7. BernYeeFaceMasks says:

    Polycationic synergists are known, reported, patented and neglected- but good for them.

    Wash your hands you heathens!

  8. Science Mechanic says:

    I am unclear on one step in the protocol: who is eating the popcorn, the mouse or the observer?

  9. lynn says:

    Just another in a long line of cationic synergists. Maybe this is better – but no breakthrough yet. [I certainly tried this approach many years ago, screening for inhibitors of both rifampicin and vancomycin against P. aeruginosa].

  10. D.V. says:

    I’m sorry I am not up to speed on all the abbreviations used in this column.
    What is a CRO? I looked up it in an acronym finder, and got 69 entries:
    Contract Research Organization, Clinical Research Organization, Conversion Rate Optimization, Clinical Research Officer, Criterion Reference Objective, Cathode Ray Oscilloscope, etc. onto 69 total meanings.
    Please, if you wish to use abbreviations, spell out the first instance of it to clarify to those not involved (who may wish to be involved) what the heck you are talking about.
    Thanks in advance. D.V.

    1. Science Mechanic says:

      Im this context, CRO is Contract Research Organization. They are used for many purposes by biopharma companies. Loupgarous is referring to their role in executing clinical trials but they are also used for many other purposes: safety studies of a drug candidate in animals, generating chemical series to explode structure-activity relationships (SAR), etc. They literally are organizations to which biopharma companies can contract out parts of their research – 20 years ago pharma companies did this all in house.

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