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New antibiotics from a marine isolate of Bacillus laterosporus Barsby, Todd

Abstract

The continued chemical investigation of a marine isolate of Bacillus laterosporus has resulted in the discovery of nine new metabolites, seven of which displayed antibiotic activity. The bogorols A - E (26-30) were found to comprise a novel structural template of the cationic peptide class of antibiotics, while the basiliskamides A and B (50 and 51) were discovered to possess potent antifungal activity versus both Candida albicans and Aspergillus fumigatus. Two structurally novel acyldipeptides, tupuseleiamides A and B (55 and 56), were the result of a serendipitous discovery. The structures in this thesis were elucidated using a combination of NMR spectroscopy, mass spectrometry, and chemical degradation coupled with chiral GC analyses. The fragmentation pattern observed in the mass spectrum of 26 allowed for the rapid structure elucidation of 27-30. An empirical method based on steric and electronic arguments was used in conjunction with a series of partial acid hydrolyses to rationalize the relative placement of the enantiomeric pairs of amino acids within the constitution of 26. A series of common structural features defined the novel bogorol cationic peptide template. The C and N termini of the linear peptides were found to be capped by an amino alcohol and an α-hydroxy acid, respectively, leaving the cationic residues to reside solely in the interior of the peptide. In addition, the bogorols contained the uncommon amino acid, E-2-amino-2-butenoic acid. A preliminary investigation of the secondary structure of the bogorols revealed their propensity to exist as ahelices, thus allowing 26-30 to adopt the amphipathic structure characteristic of cationic peptide antibiotics. The bogorols were found to exhibit in vitro antimicrobial activity versus methicillin resistant Staphylococcus aureus and vancomycin resistant Enterococcus spp. comparable to that found with other cationic peptide antibiotics. Finally, progress was made towards the total synthesis of 26. The de novo biosynthesis of 2,6-dimethyl-5-heptenal (60) by the dendronotid nudibranch, Melibe leonina, was investigated using a stable isotope incorporation experiment with [l,2-¹³C₂]acetate. This study represents the first demonstration of de novo terpene biosynthesis by a dendronotid nudibranch. As well, it is the first example to show that nudibranchs are capable of de novo monoterpene biosynthesis. The work reported with M. leonina supports recent evolutionary theory with regards to nudibranch de novo biosynthesis.

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