title: Ribosomally synthesized thiopeptide antibiotics targeting elongation factor Tu.
abstract: We identified the thiomuracins, a novel family of thiopeptides produced by a rare-actinomycete bacterium typed as a Nonomuraea species, via a screen for inhibition of growth of the bacterial pathogen Staphylococcus aureus. Thiopeptides are a class of macrocyclic, highly modified peptides that are decorated by thiazoles and defined by a central six-membered heterocyclic ring system. Mining the genomes of thiopeptide-producing strains revealed the elusive biosynthetic route for this class of antibiotics. The thiopeptides are chromosomally encoded, ribosomally synthesized proteins, and isolation of gene clusters for production of thiomuracin and the related thiopeptide GE2270A revealed the post-translational machinery required for maturation. The target of the thiomuracins was identified as bacterial Elongation Factor Tu (EF-Tu). In addition to potently inhibiting a target that is unexploited by marketed human therapeutics, the thiomuracins have a low propensity for selecting for antibiotic resistance and confer no measurable cross-resistance to antibiotics in clinical use.
authors.affiliation: Natural Products Unit, Novartis Institutes for BioMedical Research, Basel, 4056, Switzerland.
authors.forename: Rowan P
authors.initials: RP
authors.lastname: Morris
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Leeds
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Naegeli
authors.forename: Lukas
authors.initials: L
authors.lastname: Oberer
authors.forename: Klaus
authors.initials: K
authors.lastname: Memmert
authors.forename: Eric
authors.initials: E
authors.lastname: Weber
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LaMarche
authors.forename: Christian N
authors.initials: CN
authors.lastname: Parker
authors.forename: Nathalie
authors.initials: N
authors.lastname: Burrer
authors.forename: Stacey
authors.initials: S
authors.lastname: Esterow
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Hein
authors.forename: Esther K
authors.initials: EK
authors.lastname: Schmitt
authors.forename: Philipp
authors.initials: P
authors.lastname: Krastel