While people often associate the term antimicrobial resistance with bacterial pathogens, the number of fungal pathogens that are resistant to the limited number of available antifungals is rising as well (1). Of particular concern is the emergence of multidrug-resistant Candida auris, which has become resistant to all four primary classes of antifungal medication (2). 

In a recent study published in Nature, researchers at China Pharmaceutical University and Shandong University looked for new antifungals in hundreds of thousands of bacterial genomes. There, they uncovered a new antifungal that targets fungal cells using a unique mechanism — one that is resistant to resistance (3).

“Historically, we dig in the dirt, and we try to find stuff. Now there's been this huge, exciting push towards doing a kind of data driven natural product discovery. This team did that on a massive scale,” said Martin Burke, a biochemist at the University of Illinois Urbana-Champaign who was not involved in the study.

Mandimycin breaks lots of rules, and it's always fantastic when compounds come along that kind of shatter some of the norms. 
- Martin Burke, University of Illinois Urbana-Champaign

The study authors began looking for a new effective antifungal by digging through over 320,000 bacterial genomes. With fungi and bacteria coexisting in nature, often in the same habitats and competing for the same nutrients, they reasoned that bacteria could produce a potent antifungal metabolite that has not been previously identified. 

The team looked for clusters of genes responsible for making a chemical that would be structurally similar to a known antifungal, polyene. Of the four primary classes of antifungal medications — polyenes, azoles, echinocandins and pyrimidine analogue 5-flucytosine — the researchers focused on polyenes for their diverse structures, potent and broad-spectrum antifungal activities, and low likelihood of resistance development. 

They found mandimycin, a distinct 38-membered glycosylated polyene macrolide, which is a class of potent antifungal agents that disrupt fungal cell membranes by forming pores. Mandimycin contains unique structural features that differentiate it from all known polyene macrolides so far, including the commonly used polyene macrolide, amphotericin B. Mandimycin also has the highest number of deoxy sugars reported in a macrolide so far. These deoxy sugars help the antifungal dissolve 9,700 times better in water than amphotericin B, dramatically improving the bioavailability of the medication.

“There is a lot of untapped potential in this class [of antifungals],” said Arun Maji, a chemist at the University of Kentucky who was not involved in this study. Both Maji and Burke are inventors on patent applications related to glycosylated macrolide antifungals.

Next, the research team investigated mandimycin’s potency against 20 multidrug-resistant fungal isolates. Mandimycin was effective against all of these, including numerous Candida species that were resistant to all known antifungals. Furthermore, mandimycin did not result in any observable resistance. 

While the related antifungal amphotericin B is highly effective, it is also extremely toxic to the kidneys. To assess mandimycin’s toxicity, the team established two chronic fungal mice infection models of multidrug-resistant Candida albicans: a skin infection and a systemic infection. They found that mandimycin exhibited no notable markers of kidney damage, while even lower doses of amphotericin B induced stress markers. Additionally, mandimycin treatment resulted in higher animal survival rates and reduced fungal burden compared to amphotericin B.

Looking into the mechanism of mandimycin, surprisingly, the researchers found that mandimycin did not bind sterols from the fungal cell membrane like amphotericin B does, but instead it bound the phospholipids of the membrane themselves. This is a completely new mechanism of action, and one that opens a lot of questions.

“It's a very exciting breakthrough, and it really shakes things up in the area of polyene macrolides,” said Burke. Because of its structural changes and unique target, “mandimycin breaks lots of rules, and it's always fantastic when compounds come along that kind of shatter some of the norms,” Burke added. 

The study researchers stated in the paper that more work is needed to characterize mandimycin’s efficacy and whether cell membrane phospholipids could be a new drug target in antifungal development.

“It's not often that you see something switching target,” said Maji. “There is a mechanistic switch happening that we don't know how it's happening. So that's a super interesting area that I think people need to start looking into.”

References

1. CDC. Antibiotic Resistance Threats in the United States, 2019. Centers for Disease Control and Prevention (2019).
2. Spivak, E.S. & Hanson, K.E. Candida auris: an Emerging Fungal Pathogen. J Clin Microbiol  56, jcm.01588-17 (2018).
3. Deng, Q. et al. A polyene macrolide targeting phospholipids in the fungal cell membrane. Nature  640, 743–751 (2025).