Staphyloferrin A as siderophore-component in fluoroquinolone-based Trojan horse antibiotics

Stephen J Milner, Alexandra Seve, Anna M Snelling, Gavin H Thomas, Kevin G Kerr, Anne Routledge, Anne-Kathrin Duhme-Klair

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)3461-3468
Number of pages8
JournalOrganic and Biomolecular Chemistry
Volume11
Issue number21
DOIs
Publication statusPublished - 11 Apr 2013

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