title: Siderophores as drug delivery agents: application of the "Trojan Horse" strategy.
abstract: The outer membrane permeability barrier is an important resistance factor of bacterial pathogens. In combination with drug inactivating enzymes, target alteration and efflux, it can increase resistance dramatically. A strategy to overcome this membrane-mediated resistance is the misuse of bacterial transport systems. Most promising are those for iron transport. They are vital for virulence and survival of bacteria in the infected host, where iron depletion is a defense mechanism against invading pathogens. We synthesized biomimetic siderophores as shuttle vectors for active transport of antibiotics through the bacterial membrane. Structure activity relationship studies resulted in siderophore aminopenicillin conjugates that were highly active against Gram-negative pathogens which play a crucial role in destructive lung infections in cystic fibrosis patients and in severe nosocomial infections. The mechanism of action and the uptake of the compounds via specific iron siderophore transport routes were demonstrated. The novel conjugates were active against systemic Pseudomonas aeruginosa infections in mice with ED(50) values comparable to the quinolone ofloxacin and show low toxicity.
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Jena, Germany. ute.moellmann@hki-jena.de
authors.forename: Ute
authors.initials: U
authors.lastname: Möllmann
authors.forename: Lothar
authors.initials: L
authors.lastname: Heinisch
authors.forename: Adolf
authors.initials: A
authors.lastname: Bauernfeind
authors.forename: Thilo
authors.initials: T
authors.lastname: Köhler
authors.forename: Dorothe
authors.initials: D
authors.lastname: Ankel-Fuchs
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods*; D004758:Enterobactin / Q000737:chemistry; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D015242:Ofloxacin / Q000008:administration & dosage / Q000627:therapeutic use; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D017262:Siderophores / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D017262:Siderophores; D004758:Enterobactin; D015242:Ofloxacin