title: Exploiting enzymatic promiscuity to engineer a focused library of highly selective antifungal and antiproliferative aureothin analogues.
abstract: Aureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring, and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its bioactivity profile. In an integrated approach using mutasynthesis, biotransformation, and combinatorial biosynthesis, a defined library of aureothin analogues was generated. The promiscuity of the polyketide synthase assembly line toward different starter units and the plasticity of the pyrone and tetrahydrofuran ring formation were exploited. A selection of 15 new aureothin analogues with modifications at the aryl residue, the pyrone ring, and the oxygenated backbone was produced on a preparative scale and fully characterized. Remarkably, various new aureothin derivatives are less cytotoxic than aureothin but have improved antiproliferative activities. Furthermore, we found that the THF ring is crucial for the remarkably selective activity of aureothin analogues against certain pathogenic fungi.
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology, HKI, Dept. of Biomolecular Chemistry, Beutenbergstr. 11a, 07745 Jena, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Werneburg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Busch
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.forename: Martin E A
authors.initials: ME
authors.lastname: Richter
authors.forename: Longkuan
authors.initials: L
authors.lastname: Xiang
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
authors.forename: Martin
authors.initials: M
authors.lastname: Roth
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Dahse
authors.forename: Christian
authors.initials: C
authors.lastname: Hertweck
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects; D006801:Humans; D009181:Mycoses / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy; D013302:Streptomyces / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000935:Antifungal Agents; D002867:Chromones; C012198:aureothin