The endothelins (ET-1, ET-2, and ET-3) are a family of 21 amino acid peptides which contain two disulfide bonds between four cysteine residues. Two unique receptor subtypes (ETA and ETB) of ET have been identified and cloned from mammals. Elevated levels of ET-1 have been found in a number of disease states, including cardiovascular, respiratory, gastric, renal, and urological afflictions. Antagonists of the ET receptor have the potential to be safe therapeutic agents against these diseases, leading to intense efforts to discover novel antagonists to the known receptor subtypes of ET-1. From the screening of microbial extracts, we have isolated oteromycin (1), a novel antagonist of the ETB receptor, from two different strains of an unidentified fungus. Oteromycin is characterized by a bicyclic lipophilic part connected to a modified tetramic acid (hydrophilic) moiety derived from phenylalanine. Oteromycin is an antagonist of the ETB receptor (IC50 2.5 pM); it had very little effect in an angiotensin II receptor binding assay (IC50 > 25 pM). In the present study we describe the bioassay-guided isolation, structure elucidation, and biology of oteromycin (1).