Siderophores as drug delivery agents: application of the 'Trojan Horse' strategy

Autor: Lothar Heinisch, Ute Möllmann, Thilo Köhler, Adolf Bauernfeind, Dorothe Ankel-Fuchs
Rok vydání: 2008
Předmět:
Siderophore
Ofloxacin
medicine.drug_class
Antibiotics
Siderophores
medicine.disease_cause
Pseudomonas aeruginosa/drug effects
General Biochemistry
Genetics and Molecular Biology
Microbiology
Enterobactin
Biomaterials
Mice
Structure-Activity Relationship
Drug Delivery Systems
Drug Delivery Systems/methods
medicine
Animals
Humans
Pseudomonas Infections
Ofloxacin/administration & dosage/therapeutic use
Siderophores/chemistry
ddc:616
Siderophore transport
biology
Molecular Structure
Pseudomonas aeruginosa
Metals and Alloys
Anti-Bacterial Agents/administration & dosage/adverse effects/chemistry/therapeutic use
Enterobactin/chemistry
biology.organism_classification
Anti-Bacterial Agents
Biochemistry
Pseudomonas Infections/drug therapy
Drug delivery
Efflux
General Agricultural and Biological Sciences
Bacterial outer membrane
Bacteria
Zdroj: Biometals, Vol. 22, No 4 (2009) pp. 615-24
ISSN: 1572-8773
Popis: 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.
Databáze: OpenAIRE
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