A polyene macrolide targeting phospholipids in the fungal cell membrane

The global spread of multidrug-resistant pathogenic fungi presents a serious threat to human health, necessitating the discovery of antifungals with unique modes of action1. However, conventional activity-based screening for previously undescribed antibiotics has been hampered by the high-frequency rediscovery of known compounds and the lack of new antifungal targets2. Here we report the discovery of a polyene antifungal antibiotic, mandimycin, using a phylogeny-guided natural-product discovery platform. Mandimycin is biosynthesized by the mand gene cluster, has evolved in a distinct manner from known polyene macrolide antibiotics and is modified with three deoxy sugars. It has demonstrated potent and…