Production of novel lipopeptide antibiotics related to A54145 by Streptomyces fradiae mutants blocked in biosynthesis of modified amino acids and assignment of lptJ, lptK and lptL gene functions

被引：31

作者：

Alexander, Dylan C. ^{[1
]}

Rock, Jessica ^{[1
]}

Gu, Jian-Qiao ^{[1
]}

Mascio, Carmela ^{[1
]}

Chu, Min ^{[1
]}

Brian, Paul ^{[1
]}

Baltz, Richard H. ^{[1
]}

机构：

[1] Cubist Pharmaceut, Lexington, MA 02421 USA

来源：

JOURNAL OF ANTIBIOTICS | 2011年 / 64卷 / 01期

关键词：

A54145; antibiotic; combinatorial biosynthesis; lipopeptide; Streptomyces fradiae; COMBINATORIAL BIOSYNTHESIS; DAPTOMYCIN; COMPLEX; A21978C; THERAPY;

D O I：

10.1038/ja.2010.138

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

A54145 is a complex of lipopeptide antibiotics produced by Streptomyces fradiae. A54145 factors are structurally related to daptomycin, with four modified amino acids, only one of which is present in daptomycin. We generated three mutants defective in lptJ, lptK or lptL, whose gene products are involved in the formation of hydroxy-Asn(3) (hAsn(3)) and methoxy-Asp(9) (moAsp(9)). Each of the mutants produced novel lipopeptides related to A54145 and the profiles allowed assignment of functions for those genes. We constructed strains carrying different combinations of these genes coupled with a mutation in the lptl gene involved in the biosynthesis of 3-methyl-Glu(12) (3mGlu(12)), and all recombinants produced novel lipopeptides. One of the compounds displayed very good antibacterial activity in the presence of bovine surfactant, which interacts with daptomycin or A54145E to inhibit their antibacterial activities. The Journal of Antibiotics (2011) 64, 79-87; doi:10.1038/ja.2010.138; published online 24 November 2010

引用

页码：79 / 87

页数：9

共 29 条

[1] Development of a Genetic System for Combinatorial Biosynthesis of Lipopeptides in Streptomyces fradiae and Heterologous Expression of the A54145 Biosynthesis Gene Cluster [J].