Fungal polyketide engineering comes of age.

Abstract

Natural products derived from fungi have a glorious pedigree in alleviating human suffering, with penicillins being the very first microbially derived compounds to be clinically used as antibiotics. Beyond the antibiotic activity of penicillins and contemporary cephalosporins, fungal natural products exhibit extensive utility in a myriad of clinical applications. Among these, fungal polyketides offer a vast array of bioactive molecules with prominent examples including the cholesterol-lowering lovastatin, immunosuppressant mycophenolic acid, and angiogenesis inhibitor cytochalasin E (1⇓–3). Although polyketide natural products possess a comparatively higher “hit rate” for drug development (0.3%) compared with synthetic high-throughput screening libraries (<0.001%) (4), their complicated chemical structures that contain multiple stereocenters and numerous oxygen-containing substituents complicate synthetic diversity-oriented modifications (5). This structural complexity has precipitated the need to expand the chemical space naturally explored in microbes through the genetic reprogramming of secondary metabolism to yield designer molecules. Engineering of natural products via coexpression of heterologous gene combinations has been realized for bacterial polyketide antibiotics (6, 7). In PNAS, Xu et al. (8) extend this paradigm for a class of fungal polyketide natural products called the …