title: Isolation and structure elucidation of thiazomycin- a potent thiazolyl peptide antibiotic from Amycolatopsis fastidiosa.
abstract: Thiazolyl peptides are a class of rigid macrocyclic compounds richly populated with thiazole rings. They are highly potent antibiotics but none have been advanced to clinic due to poor aqueous solubility. Recent progress in this field prompted a reinvestigation leading to the isolation of a new thiazolyl peptide, thiazomycin, a congener of nocathiacins. Thiazomycin possesses an oxazolidine ring as part of the amino-sugar moiety in contrast to the dimethyl amino group present in nocathiacin I. The presence of the oxazolidine ring provides additional opportunities for chemical modifications that are not possible with other nocathiacins. Thiazomycin is extremely potent against Gram-positive bacteria both in vitro and in vivo. The titer of thiazomycin in the fermentation broth was very low compared to the nocathiacins I and III. The lower titer together with its sandwiched order of elution presented significant challenges in large scale purification of thiazomycin. This problem was resolved by the development of an innovative preferential protonation based one- and/or two-step chromatographic method, which was used for pilot plant scale purifications of thiazomycin. The isolation and structure elucidation of thiazomycin is herein described.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey, USA.
authors.forename: Hiranthi
authors.initials: H
authors.lastname: Jayasuriya
authors.forename: Kithsiri
authors.initials: K
authors.lastname: Herath
authors.forename: John G
authors.initials: JG
authors.lastname: Ondeyka
authors.forename: Chaowei
authors.initials: C
authors.lastname: Zhang
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Zink
authors.forename: Mark
authors.initials: M
authors.lastname: Brower
authors.forename: Francis P
authors.initials: FP
authors.lastname: Gailliot
authors.forename: Joyce
authors.initials: J
authors.lastname: Greene
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Birdsall
authors.forename: Jayashree
authors.initials: J
authors.lastname: Venugopal
authors.forename: Misti
authors.initials: M
authors.lastname: Ushio
authors.forename: Bruce
authors.initials: B
authors.lastname: Burgess
authors.forename: Greg
authors.initials: G
authors.lastname: Russotti
authors.forename: Andre
authors.initials: A
authors.lastname: Walker
authors.forename: Michelle
authors.initials: M
authors.lastname: Hesse
authors.forename: Anna
authors.initials: A
authors.lastname: Seeley
authors.forename: Beth
authors.initials: B
authors.lastname: Junker
authors.forename: Neal
authors.initials: N
authors.lastname: Connors
authors.forename: Oscar
authors.initials: O
authors.lastname: Salazar
authors.forename: Olga
authors.initials: O
authors.lastname: Genilloud
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.forename: Prakash
authors.initials: P
authors.lastname: Masurekar
authors.forename: John F
authors.initials: JF
authors.lastname: Barrett
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
mesh_terms: D000192:Actinomycetales / Q000737:chemistry* / Q000145:classification; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification*; D002853:Chromatography, Liquid / Q000379:methods; D005285:Fermentation; D006094:Gram-Positive Bacteria / Q000187:drug effects; D036341:Intercellular Signaling Peptides and Proteins; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification*; D012995:Solubility; D013844:Thiazoles / Q000737:chemistry / Q000302:isolation & purification*
chemical_list: D000900:Anti-Bacterial Agents; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D013844:Thiazoles; C463319:nocathiacin I; C525268:thiazomycin