Abstract
Moenomycin, a natural phosphoglycolipid product that has a long history of use in animal nutrition, is currently considered an attractive starting point for the development of novel antibiotics. We recently reconstituted the biosynthesis of this natural product in a heterologous host, Streptomyces lividans TK24, but production levels were too low to be useful. We have examined several other streptomycetes strains as hosts and have also explored the overexpression of two pleiotropic regulatory genes, afsS and relA, on moenomycin production. A moenomycin-resistant derivative of S. albus J1074 was found to give the highest titers of moenomycin, and production was improved by overexpressing relA. Partial duplication of the moe cluster 1 in S. ghanaensis also increased average moenomycin production. The results reported here suggest that rational manipulation of global regulators combined with increased moe gene dosage could be a useful technique for improvement of moenomycin biosynthesis.
MeSH Terms
Animals
Anti-Bacterial Agents/biosynthesis,isolation & purification
Bambermycins/biosynthesis,isolation & purification
Carbohydrate Sequence
Cloning, Molecular
Gene Dosage
Gene Expression Regulation, Bacterial
Genes, Regulator
Molecular Sequence Data
Streptomyces/genetics,metabolism
Streptomyces lividans/genetics,metabolism
Chemicals
Anti-Bacterial Agents
Bambermycins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Makitrynskyy Roman
Department of Genetics and Biotechnology, Ivan Franko National University of L'viv, Grushevskogo st. 4, L'viv 79005, Ukraine.
Rebets Yuriy
Ostash Bohdan
Zaburannyi Nestor
Rabyk Mariia
Walker Suzanne
Fedorenko Victor
References (29)
29 references, click to expand
-
Phosphorylated AbsA2 negatively regulates antibiotic production in Streptomyces coelicolor through interactions with pathway-specific regulatory gene promoters.
J Bacteriol. 2007 Jul;189(14):5284-92
PMID: 17513473
-
Regulation of secondary metabolism in streptomycetes.
Curr Opin Microbiol. 2005 Apr;8(2):208-15
PMID: 15802254
-
Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design.
ACS Chem Biol. 2008 Jul 18;3(7):429-36
PMID: 18642800
-
Characterization of a negative regulator AveI for avermectin biosynthesis in Streptomyces avermitilis NRRL8165.
Appl Microbiol Biotechnol. 2008 Aug;80(2):277-86
PMID: 18560830
-
Bacterial transglycosylase inhibitors.
Curr Opin Chem Biol. 2005 Oct;9(5):459-66
PMID: 16118062
-
The total synthesis of moenomycin A.
J Am Chem Soc. 2006 Nov 29;128(47):15084-5
PMID: 17117848
-
Antibacterial activity of synthetic analogues based on the disaccharide structure of moenomycin, an inhibitor of bacterial transglycosylase.
Microbiology. 2000 Dec;146 Pt 12:3129-40
PMID: 11101671
-
Inhibition of transglycosylation involved in bacterial peptidoglycan synthesis.
Curr Med Chem. 2000 Aug;7(8):801-20
PMID: 10828288
-
Genetic manipulation of antibiotic-producing Streptomyces.
Trends Microbiol. 1998 Feb;6(2):76-83
PMID: 9507643
-
[Analysis of genome rearrangements in Streptomyces kanamyceticus mutants].
Antibiot Khimioter. 1998;43(4):14-9
PMID: 9606499
-
afsR is a pleiotropic but conditionally required regulatory gene for antibiotic production in Streptomyces coelicolor A3(2).
Mol Microbiol. 1996 Jul;21(2):385-96
PMID: 8858592
-
Identifying bacterial genes and endosymbiont DNA with Glimmer.
Bioinformatics. 2007 Mar 15;23(6):673-9
PMID: 17237039
-
Streptomyces albus G mutants defective in the SalGI restriction-modification system.
J Gen Microbiol. 1980 Feb;116(2):323-34
PMID: 6246193
-
Coordination of export and glycosylation of landomycins in Streptomyces cyanogenus S136.
FEMS Microbiol Lett. 2008 Aug;285(2):195-202
PMID: 18537830
-
Complete characterization of the seventeen step moenomycin biosynthetic pathway.
Biochemistry. 2009 Sep 22;48(37):8830-41
PMID: 19640006
-
Cross-regulation among disparate antibiotic biosynthetic pathways of Streptomyces coelicolor.
Mol Microbiol. 2005 Dec;58(5):1276-87
PMID: 16313616
-
Basic local alignment search tool.
J Mol Biol. 1990 Oct 5;215(3):403-10
PMID: 2231712
-
Induction of actinorhodin production by rpsL (encoding ribosomal protein S12) mutations that confer streptomycin resistance in Streptomyces lividans and Streptomyces coelicolor A3(2).
J Bacteriol. 1996 Dec;178(24):7276-84
PMID: 8955413
-
Effect of a global regulatory gene, afsR2, from Streptomyces lividans on avermectin production in Streptomyces avermitilis.
J Biosci Bioeng. 2000;89(6):606-8
PMID: 16232806
-
Identification and characterization of Streptomyces ghanaensis ATCC14672 integration sites for three actinophage-based plasmids.
Plasmid. 2009 May;61(3):171-5
PMID: 19167423
-
A gene transfer system for the glycopeptide producer Nonomuraea sp. ATCC39727.
FEMS Microbiol Lett. 2003 Aug 8;225(1):53-7
PMID: 12900021
-
A streamlined metabolic pathway for the biosynthesis of moenomycin A.
Chem Biol. 2007 Mar;14(3):257-67
PMID: 17379141
-
Functional analysis of relA and rshA, two relA/spoT homologues of Streptomyces coelicolor A3(2).
J Bacteriol. 2001 Jun;183(11):3488-98
PMID: 11344157
-
Structural insight into the transglycosylation step of bacterial cell-wall biosynthesis.
Science. 2007 Mar 9;315(5817):1402-5
PMID: 17347437
-
Genome-wide transcriptome analysis reveals that a pleiotropic antibiotic regulator, AfsS, modulates nutritional stress response in Streptomyces coelicolor A3(2).
BMC Genomics. 2008;9:56
PMID: 18230178
-
The biosynthetic gene cluster for the antitumor rebeccamycin: characterization and generation of indolocarbazole derivatives.
Chem Biol. 2002 Apr;9(4):519-31
PMID: 11983340
-
One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products.
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6640-5
PMID: 10829079
-
afsR2: a previously undetected gene encoding a 63-amino-acid protein that stimulates antibiotic production in Streptomyces lividans.
Mol Microbiol. 1994 Nov;14(4):643-53
PMID: 7891553
-
Amplification of the entire kanamycin biosynthetic gene cluster during empirical strain improvement of Streptomyces kanamyceticus.
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9661-6
PMID: 16766657