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!