As fungi resistant to traditional treatments continue to spread around the globe, researchers from China Pharmaceutical University in Nanjing have identified a bacterial compound that can kill infectious fungi even if they’re resistant to other antifungals.
The discovery of the compound, called mandimycin, was reported in Nature on March 19.
To test mandimycin’s potency, the researchers grew a suite of drug-resistant fungi in tiny wells of broth and then exposed them to the compound. Notable fungi that mandimycin successfully stomped out include species of Candida, Cryptococcus neoformans and Aspergillus fumigatus, according to the team.
The newfound compound was even able to treat mice infected with a strain of Candida auris that is resistant to all major types of antifungals, a growing public health concern.
Candida are yeast that occur normally in parts of the body, but they can cause infections called candidiasis when they stray beyond their normal bounds. Serious invasive infection can occur if the fungi reach the bloodstream, heart or skull, which is especially a concern for immunocompromised patients.
Cryptococcus neoformans, meanwhile, forms spores that can cause lung or brain infections when breathed in. And Aspergillus fumigatus, a kind of mold, can also cause respiratory infections when inhaled.
The fungi tested came from the World Health Organization’s fungal priority pathogens list, which includes infectious fungi with significant unmet need and public health importance. All the screened fungi were resistant to between two and four existing drugs.
Mandimycin is a polyene macrolide within the polyene class of antifungals. Aside from polyenes, there are two other main antifungal classes: azoles and echinocandins. Though it’s a polyene, mandimycin has a unique mechanism for killing fungal cells: It binds to phospholipids in the fungal cell’s membrane, causing potassium to leak out of the cell and ultimately collapsing the membrane.
Other polyene macrolides, including one from Elion Therapeutics currently in a phase 1 trial, instead bind to a different kind of membrane lipid called ergosterol. Fungi don’t develop resistance to this group of molecules easily, but the mandimycin discoverers were able to culture fungi in the lab that were resistant to them, including to amphotericin B, which is the basis for Elion’s asset SF001. Elion developed SF001 under its earlier name, Sfunga Therapeutics.
No matter how much mandimycin the fungi were exposed to, however, they never developed resistance to it, the authors reported.
The researchers identified mandimycin by extensively scouring the genomes of 316,123 bacteria from the National Institutes of Health’s National Center for Biotechnology Information, including 150 from the Streptomyces species. Bacteria living in the environment compete with fungi for resources, so they often evolve chemicals to snuff them out.
Scrutinizing the evolutionary relationships of the polyene macrolides made by these bacteria led to the discovery of a chemical group that seemed very different from other polyenes, according to the researchers. Within this group of chemicals, made by a strain of the bacteria Streptomyces netropsis, was mandimycin.
The approach “is like hacking two billion years of archived files from the global bacterial military’s central command and placing them in chronological order,” chemists Arun Maji, Ph.D., and Martin Burke, Ph.D., wrote in a perspective article published alongside the new paper. “The authors then strategically searched for what could be imagined as a relatively modern file, perhaps labelled ‘top-secret weapon for overcoming fungal resistance’—which would contain the instructions for making mandimycin.”