Mandimycin: A polyene antifungal with a unique mode of action

Fungal infections may not be as common as bacterial or viral infections, but they can still be deadly. And the deadliest pathogenic fungi, such as Candida auris, are becoming increasingly resistant to approved antifungals, which is why researchers are on the hunt for new antifungal compounds.

Enter a new antifungal, mandimycin. It’s the latest addition to a group of antifungals called glycosylated polyene macrolides, but it works differently from the rest. That could help it evade resistance, say its discoverers (Nature 2025, DOI: 10.1038/s41586-025-08678-9).

Mandimycin is structurally similar to the last-line-of-defense antifungal amphotericin B, another glycosylated polyene macrolide. But instead of binding to ergosterol in the fungal cell membrane as amphotericin B does, mandimycin binds to the phospholipids, creating holes in the membrane that lead to cell death.

Martin Burke, a chemist at the University of Illinois Urbana-Champaign who wasn’t involved in the research, calls the discovery a “big surprise” and says that this work signals the start of a “renaissance happening in glycosylated polyene macrolides.”

The research was led by Qisen Deng of China Pharmaceutical University. Deng and collaborators discovered mandimycin through something they call a “phylogeny-guided natural-product discovery platform.” The team compared thousands of gene sequences of bacterial glycosyltransferases that attach an amino sugar mycosamine to a macrolide skeleton. That allowed them to identify a group of bacteria not previously known to produce polyene macrolide compounds. And those bacteria make the polyene macrolide mandimycin.

Chad Rienstra, a biochemist at the University of Wisconsin–Madison who was not involved with the research, says the key to mandimycin’s unique phospholipid binding affinity is a “dideoxy sugar moiety.” This sugar group is the major difference between mandimycin and amphotericin B.

It’s still unclear why the sugar group drastically changes the binding properties of the molecule so that it interacts with a different target. But Rienstra says that another glycosylated polyene macrolide, selvamicin, has a sugar group in the same place as mandimycin that changes its binding characteristics compared with those of amphotericin B.

In vitro and in vivo mouse experiments demonstrated that mandimycin is effective at killing amphotericin B–resistant strains of C. auris and other fungal pathogens. Further testing suggested that mandimycin is also less toxic than amphotericin B, often referred to by doctors as “ampho-terrible B” because of its side effects for patients.

Burke says that in addition to binding to ergosterol in fungal cells, amphotericin B can bind to cholesterol in human cells, which is why that drug is so toxic. Mandimycin, on the other hand, binds phospholipids that are present in both fungi and humans. “And yet, it’s somewhat less toxic than amphotericin B,” he says. That difference in toxicity is “a mystery that’s going to require a lot more study to understand.”

Despite the researchers’ findings that mandimycin has limited toxicity and is effective at killing pathogenic fungi, Rienstra says that it’s “a little bit premature to make conclusions about a clinical application” for the new compound. And it may be that other, yet undiscovered, sugar-modified polyene macrolides end up being more effective and less toxic for human use.

But Rienstra says the work is still impactful and that it both “proposes a new mode of action for a category of glycosylated polyene macrolides that hasn't been previously reported and provides a new avenue to pursue antifungal drug development complementary to existing clinical drugs.”