1 ) Medium optimization of Streptomyces sp . 17944 for tirandamycin B production and isolation and structural elucidation of tirandamycins H , I , and

We have recently isolated tirandamycin (TAM) B from Streptomyces sp. 17944 as a Brugia malayi AsnRS (BmAsnRS) inhibitor that efficiently kills the adult B. malayi parasites and does not exhibit general cytotoxicity to human hepatic cells. We now report (i) the comparison of metabolite profiles of S. sp. 17944 in six different media, (ii) identification of a medium enabling the production of TAM B as essentially the sole metabolite, and with improved titer, and (iii) isolation and structural elucidation of three new TAM congeners. These findings shed new insights into the structure-activity relationship of TAM B as a BmAsnRS inhibitor, highlighting the δ-hydroxymethyl-α,β-epoxyketone moiety as the critical pharmacophore, and should greatly facilitate the production and isolation of sufficient quantities of TAM B for further mechanistic and preclinical studies to advance the candidacy of TAM B as an antifilarial drug lead. The current study also serves as an excellent reminder that traditional medium and fermentation optimization should continue to be very effective in improving metabolite flux and titer. †Dedicated to Professor Christopher T. Walsh, Harvard Medical School for his enormous impact on the field of antibiotic and microbial natural product biosynthesis. Users may view, print, copy, download and text and datamine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms To whom correspondence should be addressed: Ben Shen, The Scripps Research Institute, 130 Scripps Way, #3A1, Jupiter, Florida 33458, United States. Tel: (561) 228-2456, Fax: (561) 228-2472, [email protected]. Supplementary Information Available General experimental procedures, sequence comparison among TamI/TrdI from S. sp. 307-9, S. sp. SCSIO 1666, and S. sp. 17944 (Figure S1), and HRESIMS and 1H and 13C NMR spectra of 6, 7, and 8 (Figures S2-10). This material is available free of charge via the Internet at http://www.nature.com/ja. HHS Public Access Author manuscript J Antibiot (Tokyo). Author manuscript; available in PMC 2014 July 01. Published in final edited form as: J Antibiot (Tokyo). 2014 January ; 67(1): 127–132. doi:10.1038/ja.2013.50. A uhor M anscript