An Artificial Pathway to 3,4-Dihydroxybenzoic Acid Allows Generation of New Aminocoumarin Antibiotic Recognized by Catechol Transporters of E. coli

被引：19
作者：
Alt, Silke [1 ]
Burkard, Nadja [2 ]
Kulik, Andreas [3 ]
Grond, Stephanie [2 ]
Heide, Lutz [1 ]
机构：
[1] Univ Tubingen, Inst Pharmazeut, D-72076 Tubingen, Germany
[2] Univ Tubingen, Inst Organ Chem, D-72076 Tubingen, Germany
[3] Univ Tubingen, Inst Mikrobiol, D-72076 Tubingen, Germany
来源：
CHEMISTRY & BIOLOGY | 2011年 / 18卷 / 03期
关键词：
STREPTOMYCES-COELICOLOR A3(2); BIOSYNTHETIC GENE CLUSTERS; ESCHERICHIA-COLI; CORYNEBACTERIUM-GLUTAMICUM; CLOROBIOCIN BIOSYNTHESIS; HETEROLOGOUS EXPRESSION; COUMERMYCIN A(1); IN-VITRO; IRON; SIDEROPHORES;
D O I：
10.1016/j.chembiol.2010.12.016
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
An artificial operon was synthesized, consisting of the genes for chorismate pyruvate-lyase of E. coli and for 4-hydroxybenzoate 3-hydroxylase of Colyne-bacterium cyclohexanicum. This operon, directing the biosynthesis of 3,4-dihdroxybenzoate, was expressed in the heterologous expression host Streptomyces coelicolor M512, together with a modified biosynthetic gene cluster for the aminocoumarin antibiotic clorobiocin. The resulting strain produced a clorobiocin derivative containing a 3,4-dihdroxy-benzoyl moiety. Its structure was confirmed by MS and NMR analysis, and it was found to be a potent inhibitor of the gyrases from Escherichia coli and Staphylococcus aureus. Bioassays against different E. coli mutants suggested that this compound is actively imported by catechol siderophore transporters in the cell envelope. This study provides an example of the structure of a natural product that can be rationally modified by synthetic biology.
引用
收藏
页码：304 / 313
页数：10
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