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A New Fungal Fighter

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When one thinks of fungi, mushrooms or bread molds typically come to mind. However, there are some fungal species that cause human illness, either through allergic responses or life-threatening systemic infections. Fungal infections, in general, affect over 1 billion people worldwide every year, yet more worrisome are the rising rates of multidrug resistance in these pathogens. There are only 4 types of antifungals currently used on the market, the polyenes, azoles, echinocandins and the pyrimidine analogue 5-flucytosine, each with marked cases of resistance. Researchers have found a new antifungal called mandimycin, that outperforms similar chemicals in both in vitro and in vivo studies.

A collaborative team of scientists from China Pharmaceutical University and Shandong University, set out to find a novel antifungal that has reduced resistance. To get started, they focused on the polyene class of antifungals, as they boast the most structural and functional diversity, and started digging through over 316,123 bacterial genomes from the NCBI database, as well as 150 Streptomyces genomes, stored in house. Their mission was to identify genes that are predictive of polyene synthesis, specifically putative mycosamine-transferring glycosyltransferases that are known to make polyenes. If they could find the enzymes, they could identify new compounds that may have antifungal properties.

They identified a unique gene cluster, from antibiotic producing powerhouse Streptomyces netropsis, that had promising potential to produce a polyene metabolite. They grew the bacteria and used advanced tools to identify a compound that matched what they were looking for. It turned out to be a unique compound called mandimycin. What makes mandimycin stand out is its unique structure, which sets it apart from other similar antibiotics, including the well-known drug amphotericin B.

The researchers tested mandimycin against a panel of priority fungal pathogens recommended by the World Health Organization. Mandimycin showed strong activity against all fungal isolates, and no observed resistance, while other antifungals tested had at least 2 resistant isolates. The team was curious about how mandimycin affects bacterial pathogens, and found this drug to be strictly antifungal, pointing them towards the mechanism of action.

To understand how this polyene was so effective, the researchers used Candida albicans to explore the drug target. They found the drug to be fungicidal, ultimately killing the fungi instead of stopping growth.They were interested in the fungal cell membrane, as that is how other polyenes attack. They found that after treatment of mandimycin, the fungi experienced a rapid loss of potassium ions that ultimately led to the cell membrane collapsing.

Since other polyenes target the sterols in the membrane, the team wondered if mandimycin might target a different cell membrane component. They tested cell membrane proteins, glycans, sterols, and lipids, for their binding ability to mandimycin. They found that only phospholipids bound to mandimycin, and this interaction far surpassed the binding of amphotericin B and its target, ergosterol. These findings confirmed that mandimycin exerts its fungicidal activity by specific binding to various phospholipids, leading to ion leakage and subsequent cell collapse. This is a completely new way in which polyenes can effectively kill fungal cells.

Mandimycin has a unique mechanism of action, binding phospholipids instead of sterols in fungal membranes.
Credit: https://www.nature.com/articles/d41586-025-00801-0.

Kidney injury and haemolysis are common and severe side effects associated with the use of polyene antifungals, so the researchers tested if mandimycin treatment also shared these effects. First, they tested the potency and toxicity using human renal proximal tubular epithelial (HK-2) cells and human primary renal proximal tubule epithelial cells (RPTEC), as well as other human cell lines (that is, HepG2, PANC-1 and SK-Hep1). They found the negative effects were 7-22x less than other polyenes tested.

With promising results, the researchers moved into mouse models. They examined specific kidney damage-related biomarkers and tissue morphology, and found mandimycin did not induce any changes, even at a high dose, while amphotericin B treatment induced noticeable kidney damage.

Finally, the researchers tested mandimycin for its therapeutic effects. They developed multiple types of chronic fungal infections mouse models, and tested how well mandimycin was able to clear the infection. Mandimycin reduced the infection by about 200 times from the mice, while other polyenes made little difference.

This research marks a giant step forward in the development of new, effective, and non-toxic antifungals, and presents fungal phospholipids as an appealing target for drug discovery.

Link to the original post: Deng, Q., Li, Y., He, W. et al. A polyene macrolide targeting phospholipids in the fungal cell membrane. Nature (2025).

Featured image: New antibiotic targets fungi by attacking the lipids in cell membranes. Image made by Megan Keller using BioRender.com.