ABSTRACT
Two new peptaibols, septocylindrin A (1) and septocylindrin B (2), related to the well-studied membrane-channel-forming peptaibol alamethicin, were obtained from a terrestrial isolate of the fungus Septocylindrium sp. Both 1 and 2 are linear 19-amino acid peptides with a modified phenylalanine C-terminus. Analysis of the HRMS data indicated that they differ only in the 18th residue, where 1 contains Glu and 2 contains Gln. The structures of these two peptaibols were determined by extensive NMR and HRMS analysis. The absolute configurations of amino acids present in 1 were determined using Marfey's methodology. Both compounds were isolated through bioassay-guided fractionation and exhibited significant antibacterial and antifungal activity.
Subject(s)
Anti-Bacterial Agents , Antifungal Agents/isolation & purification , Fungi/chemistry , Peptides/isolation & purification , Alamethicin/chemistry , Amino Acid Sequence , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Microbial Sensitivity Tests , Molecular Sequence Data , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Peptaibols , Peptides/chemistry , Peptides/pharmacologyABSTRACT
3-Normeridamycin (1), isolated from fermentation extracts of the soil actinomycete Streptomyces sp. LL-C31037, demonstrated potent neuroprotective activity. When challenged with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), known to induce parkinsonism, 1 restored functional dopamine uptake in a concentration-dependent manner, with an EC50 of 110 nM in dopaminergic neurons. The structure of 1 was determined via spectroscopic methods, and the immunosuppressive and immunophilin binding properties of the compound were also measured.
Subject(s)
Antiparkinson Agents/isolation & purification , Immunophilins/metabolism , Macrolides/isolation & purification , Neuroprotective Agents/isolation & purification , Streptomyces/metabolism , Antiparkinson Agents/chemistry , Antiparkinson Agents/pharmacology , Humans , Ligands , Macrolides/chemistry , Macrolides/pharmacology , Neuroprotective Agents/chemistry , Neuroprotective Agents/pharmacology , Streptomyces/classificationABSTRACT
The natural product rapamycin, produced during fermentation by Streptomyces hygroscopicus, is known for its potent antifungal, immunosuppressive, and anticancer activities. During rapamycin biosynthesis, the amino acid l-pipecolate is incorporated into the rapamycin molecule. We investigated the use of precursor-directed biosynthesis to create new rapamycin analogs by substitution of unusual l-pipecolate analogs in place of the normal amino acid. Our results suggest that the l-pipecolate analog (+/-)-nipecotic acid inhibits the biosynthesis of l-pipecolate, thereby limiting the availability of this molecule for rapamycin biosynthesis. We used (+/-)-nipecotic acid in our precursor-directed biosynthesis studies to reduce l-pipecolate availability and thereby enhance the incorporation of other pipecolate analogs into the rapamycin molecule. We describe here the use of this method for production of two new sulfur-containing rapamycin analogs, 20-thiarapamycin and 15-deoxo-19-sulfoxylrapamycin, and report measurement of their binding to FKBP12.
Subject(s)
Gene Expression Regulation, Bacterial , Protein Precursors/metabolism , Sirolimus/analogs & derivatives , Sirolimus/metabolism , Streptomyces/metabolism , Biotechnology/methods , Nipecotic Acids/metabolism , Pipecolic Acids/metabolism , Streptomyces/genetics , Streptomyces/growth & development , Tacrolimus Binding Protein 1A/metabolismABSTRACT
[reaction: see text] Two novel sulfur-containing analogs of the immunosuppressive natural product rapamycin (1) were obtained by feeding cultures of Streptomyces hygroscopicus with l-nipecotic acid (4) and either (S)-1,3-thiazane-4-carboxylic acid (5) or (S)-1,4-thiazane-3-carboxylic acid (6). The structures of the two new compounds, 20-thiarapamycin (2) and 15-deoxo-19-sulfoxylrapamycin (3), were determined by spectroscopic methods.
