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

• Published in: Organic & biomolecular chemistry 2013-06, Vol.11 (21), p.3461-3468
• Main Authors: Milner, Stephen J, Seve, Alexandra, Snelling, Anna M, Thomas, Gavin H, Kerr, Kevin G, Routledge, Anne, Duhme-Klair, Anne-Kathrin
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacteria - drug effects; Carboxylic Acids - chemistry; Citrates - chemistry; Fluoroquinolones - chemical synthesis; Fluoroquinolones - chemistry; Fluoroquinolones - pharmacology; Humans; Models, Molecular; Ornithine - analogs & derivatives; Ornithine - chemistry; Siderophores - chemistry
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c3ob40162f

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.