ABSTRACT
A new bacterium, Saccharopolyspora pogona (NRRL30141) was discovered which produced a series of very potent insecticidal compounds structurally related to the 'classical' (i.e., C-21-ethyl) spinosyns. A series of fermentations gave sufficient extract to allow the isolation and characterization of a total of 31 new metabolites. The majority of these compounds contained a but-1-enyl group at C-21 of the macrolide in place of the ethyl group in the 'classical' spinosyn series, corresponding to an additional acetate group incorporated during their biosynthesis. Additionally a variety of other new functionality was seen including hydroxylations, several novel forosamine sugar replacements, and a novel 14-membered macrolide ring analog.
Subject(s)
Insecticides/chemistry , Macrolides/chemistry , Saccharopolyspora/chemistry , Chromatography, Liquid , Drug Discovery , Fermentation , Insecticides/isolation & purification , Insecticides/pharmacology , Macrolides/isolation & purification , Macrolides/pharmacology , Mass SpectrometryABSTRACT
The spinosyns are a family of potent and highly selective insect control agents that display a favorable environmental profile. As some regions of the spinosyn molecule are recalcitrant to chemical modification, a targeted genetic approach was carried out to generate new analogues. The polyketide synthase (PKS) loading modules from the avermectin PKS of Streptomyces avermitilis and the erythromcyin PKS of Saccharopolyspora erythraea were each used to replace the spinosyn PKS loading module. Both of the resulting strains containing hybrid PKS pathways produced the anticipated spinosyn analogues. Supplementation of the culture media with a range of exogenous carboxylic acids led to the successful incorporation of these novel elements to yield further novel spinosyn molecules, some of which demonstrated potent and new insecticidal activities. Furthermore, it has been demonstrated that semisynthesis of such novel metabolites can then be used to generate active analogues, demonstrating the effectiveness of utilizing these complementary methods to search the chemical space around this template.
Subject(s)
DNA/chemistry , Insecticides/chemistry , Macrolides/chemistry , Polyketide Synthases/chemistry , Tetranychidae/drug effects , Amino Acid Sequence , Animals , Base Sequence , Erythromycin/chemistry , Escherichia coli/metabolism , Ivermectin/analogs & derivatives , Ivermectin/chemistry , Models, Molecular , Protein Engineering , Saccharopolyspora/enzymology , Saccharopolyspora/metabolism , Streptomyces/enzymology , Streptomyces/metabolismABSTRACT
Several Penicillia and one Tricothecium strain produced a new, insecticidally active member of the cycloaspeptide family, with the proposed name cycloaspeptide E (1). The structure, which was determined on the basis of spectroscopic (NMR, UV, MS) data and Marfey amino acid analysis, was the tyrosine desoxy version of cycloaspeptide A (2). Two synthetic routes to compound 1 were developed: one a partial synthesis from 2 and the other a total synthesis from methyl alaninate hydrochloride. Cycloaspeptide E, the first member of this series not to contain a tyrosine moiety, is also the first to be reported with insecticidal activity.
Subject(s)
Ascomycota/chemistry , Insecticides , Lepidoptera/drug effects , Penicillium/chemistry , Peptides, Cyclic , Animals , Insecticides/chemical synthesis , Insecticides/chemistry , Insecticides/isolation & purification , Insecticides/pharmacology , Molecular Structure , Peptides, Cyclic/chemistry , Peptides, Cyclic/isolation & purification , Peptides, Cyclic/pharmacology , Structure-Activity RelationshipABSTRACT
A new member of the tartrolone series of macrodiolides, tartrolone C (1), was isolated from a Streptomyces species on the basis of its insecticidal activity. Metacycloprodigiosin (2) and undecylprodigiosin (3) were also isolated on the same basis. The structure of all compounds was established by spectroscopic data (NMR, MS, and UV).
