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Tagging Fungi For Destruction

Fungal infections can be very bad news when they go beyond the get-something-from-the-drugstore stage. That fact that a drug as rough as amphotericin B is still in use is evidence enough of that. There’s definitely a need for new ideas in the antifungal area, but drug discovery there has been tough. This new paper, though, takes an approach that hasn’t been tried in the antifungal area until now.

Since fungi are eukaryotes, there aren’t as many opportunities to find nonhuman targets as there are in antibacterial work (not that that’s not hard enough already). One big lever, though, is the way that fungi (and some other organisms) use ergosterol instead of cholesterol in their cell membranes – all the “-onazole” antifungal drugs work by disrupting ergosterol synthesis, while amphotericin and related agents bind to it in the membrane itself. Chitin, meanwhile, is a key component of the fungal cell wall, but finding drugs that target chitin synthesis has not been that rewarding so far, frustratingly. Nikkomycin is one such, although it’s apparently not very broad-spectrum, and it’s still in development.

This latest work, from Yale, Merck, and Prokaryotics, is also targeting chitin, but in a very different way. They’re using a strategy that they’ve applied to cancerous cells and to antiviral therapy, which is making a bifunctional antibody-recruitment molecule. One end binds to a motif on the desired target, and the other end is a known signal for antibody binding. In this case, the target binding end is based on calcofluor, which is known as a fluorescent stain for chitin in microscopy. A standard problem in such ideas is finding a place to attach a linking group, but one end of the calcofluor molecule seemed to be amenable to substitution.

And the strategy does seem to work – antibodies are recruited to C. albicans cells, and neutrophils then clear them in vitro. There’s also an interesting combination idea, with another antifungal class, the echinocandins. Those disrupt glucan formation, another cell-well component, and resistant fungi often compensate by cranking up chitin formation. But a combination of an echinocandin and this antibody-recruitment compound was even more effective than before. This paper only looked at yeast cells, but since chitin is a component of every fungus, you’d expect it to work against the other fungal pathogens as well.

So this is a solid proof-of-concept, but any drug discovery person who reads the paper will know what the next questions are: does it work in an animal? How can molecules like this be dosed? Are there side effects in vivo? And so on. This paper doesn’t go into those questions, naturally, but I hope that answers are being sought with this compound or related ones. It would seem pretty straightforward to set up a chitin-binding screen, for example, to look for other chemical motifs than calcofluor, which may not be the most bioavailable thing on the planet. That sort of screen may not have been explored much, since for a drug you’d be looking for inhibitors of chitin formation itself, not just things that stick to the finished product. In that way, this approach is reminiscent of the currently hot topic of targeted protein degradation, where you also make bifunctional molecules that need binding groups on their business ends. In both cases, if all you need is something that binds, rather than some further function, that opens the field up a bit. Worth watching!

10 comments on “Tagging Fungi For Destruction”

  1. roger says:

    The shade of Dr. Ehrlich smiles. Only 606 more iterations…

  2. Interestingly, the latest issue of Nat Rev Drug Discovery has a review on what the author calls a “robust and dynamic” antifungal pipeline (linked in my handle).

  3. Barry says:

    Since fungal pathogens do display such distinct, conserved, surface motifs, why should we need these immune system prostheses rather than focusing on anti-fungal vaccines?

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708015/

    1. NJBiologist says:

      Proteins are usually the best antigens, and usually by a wide margin. Polysaccharides (like chitin) and lipids tend to be really tough to develop vaccines for.

      That doesn’t rule out other surface proteins, but it does take away the broadest-spectrum opportunities.

  4. Barry says:

    And if we’re relying on recruiting a neutrophil response, are we missing the immune-deficient population that is more at risk of fungal infections? Or is there a population in whom B-cell and neutrophil response is competent, but who are deficient in other aspects of immunity?

  5. Thomas Lumley says:

    The ‘onazole’ drugs (and the allylamines) get described as selective because they target ergosterol synthesis, but don’t they target steps that are common to cholesterol synthesis too? They just inhibit the fungal version of the enzyme better than the mammalian version.

  6. Microscopic Buddy says:

    We always go to become more than the drugstore stage….derrr

  7. Jake says:

    I don’t know anything about medicine so apologies if this thought is dumb, but there’s a lot of chitin-having arachnids out there in places we don’t always expect (the first two examples that come to mind are skin mites and flour beetles)

  8. Jb says:

    Anyone else see this:

    https://www.chemistryworld.com/news/fake-peer-review-hits-rsc-journals/3007911.article

    RSC has gotten rocked with authors setting up fake emails to front as a review in order to do their own ‘peer review’. Multiple papers retracted.

  9. Paula Sundstrom says:

    While chitin has been the target of previous research on anti fungal drug development, the recruitment of endogenous host antibodies to opsonize fungi using ARM-Fs has not been tested. Future research showing efficacy for filamentous forms of fungi as well as yeast forms and for demonstrating therapeutic efficacy in animal models is worth watching given that few anti fungal drugs are available for treating serious fungal disease.

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