title: Medium optimization of Streptomyces sp. 17944 for tirandamycin B production and isolation and structural elucidation of tirandamycins H, I and J.
abstract: 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.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Mostafa E
authors.initials: ME
authors.lastname: Rateb
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Yu
authors.affiliation: 1] Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA [2] School of Life Science, Northeast Agricultural University, Harbin, China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Huang
authors.affiliation: Biotechnology and Bioengineering Center and Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Sanja
authors.initials: S
authors.lastname: Vodanovic-Jankovic
authors.affiliation: Biotechnology and Bioengineering Center and Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kron
authors.affiliation: 1] Department of Chemistry, The Scripps Research Institute, Jupiter, FL, USA [2] Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA [3] Natural Products Library Initiative, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000302:isolation & purification; D003470:Culture Media / Q000737:chemistry*; D015195:Drug Design; D005285:Fermentation; D005369:Filaricides / Q000737:chemistry / Q000302:isolation & purification; D013302:Streptomyces / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D003470:Culture Media; D005369:Filaricides; C021492:tirandamycin B