title: Confronting the challenges of natural product-based antifungal discovery.
abstract: Starting with the discovery of penicillin, the pharmaceutical industry has relied extensively on natural products (NPs) as an unparalleled source of bioactive small molecules suitable for antibiotic development. However, the discovery of structurally novel and chemically tractable NPs with suitable pharmacological properties as antibiotic leads has waned in recent decades. Today, the repetitive "rediscovery" of previously known NP classes with limited antibiotic lead potential dominates most industrial efforts. This limited productivity, exacerbated by the significant financial and resource requirements of such activities, has led to a broad de-emphasis of NP research by most pharmaceutical companies, including most recently Merck. Here we review our strategies--both technological and philosophical--in addressing current antifungal discovery bottlenecks in target identification and validation and how such efforts may improve NP-based antimicrobial discoveries when aligned with NP screening and dereplication.
authors.affiliation: Department of Infectious Disease, Merck Frosst Canada Ltd., Montreal, QC, Canada. terry_roemer@merck.com
authors.forename: Terry
authors.initials: T
authors.lastname: Roemer
authors.forename: Deming
authors.initials: D
authors.lastname: Xu
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Craig A
authors.initials: CA
authors.lastname: Parish
authors.forename: Guy
authors.initials: G
authors.lastname: Harris
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Julian E
authors.initials: JE
authors.lastname: Davies
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Bills
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D006801:Humans
chemical_list: D000935:Antifungal Agents; D001688:Biological Products