title: Staphyloferrin A as siderophore-component in fluoroquinolone-based Trojan horse antibiotics.
abstract: A series of fluoroquinolone conjugates was synthesised by linking the carboxylic acid functionality of the carboxylate-type siderophore staphyloferrin A and its derivatives to the piperazinyl nitrogen of ciprofloxacin and norfloxacin via amide bond formation. Four siderophore-drug conjugates were screened against a panel of bacteria associated with infection in humans. Whilst no activity was found against ciprofloxacin- or norfloxacin-resistant bacteria, one of the conjugates retained antibacterial activity against fluoroquinolone-susceptible strains although the structure of its lysine-based siderophore component differs from that of the natural siderophore staphyloferrin A. In contrast, three ornithine-based siderophore conjugates showed significantly reduced activity against strains that are susceptible to their respective parent fluoroquinolones, regardless of the type of fluoroquinolone attached or chirality at the ornithine Cα-atom. The loss of potency observed for the (R)- and (S)-ornithine-based ciprofloxacin conjugates correlates with their reduced inhibitory activity against the target enzyme DNA gyrase.
authors.affiliation: Department of Chemistry, University of York, Heslington, York YO10 5DD, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Milner
authors.forename: Alexandra
authors.initials: A
authors.lastname: Seve
authors.forename: Anna M
authors.initials: AM
authors.lastname: Snelling
authors.forename: Gavin H
authors.initials: GH
authors.lastname: Thomas
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Kerr
authors.forename: Anne
authors.initials: A
authors.lastname: Routledge
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Duhme-Klair
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D002264:Carboxylic Acids / Q000737:chemistry; D002951:Citrates / Q000737:chemistry*; D024841:Fluoroquinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D009952:Ornithine / Q000031:analogs & derivatives* / Q000737:chemistry; D017262:Siderophores / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D002951:Citrates; D024841:Fluoroquinolones; D017262:Siderophores; C063851:staphyloferrin A; D009952:Ornithine