title: Various routes of administration of (99m)Tc-labeled synthetic lactoferrin antimicrobial peptide hLF 1-11 enables monitoring and effective killing of multidrug-resistant Staphylococcus aureus infections in mice.
abstract: The synthetic antimicrobial peptide representative of the first 11 N-terminal amino acids of human lactoferrin (hLF 1-11) kills multidrug-resistant Staphylococcus aureus (MRSA). This study displays antimicrobial activity of hLF 1-11, via various routes of administration, against MRSA infections in mice. Radiolabeling hLF 1-11 with technetium-99m ((99m)Tc-hLF 1-11) enables scintigraphic monitoring directly after administration. (99m)Tc-hLF 1-11 was taken up by the gall bladder, intestines, and kidneys. Most of the radioactivity was captured in the urinary bladder and about 1% of the injected dose accumulated into infected thigh muscles. At 2 or 24h after either intravenously, subcutaneously, intraperitoneally, or orally injected a single dose of 0.04 mg/kg hLF 1-11 in mice significantly reduced (20-60 times) the number of viable MRSA. In a dose-response setting in immunocompetent mice maximum bactericidal effects (10,000 times reduction) of intravenously injected (99m)Tc-hLF 1-11 was seen with 40 mg/kg whereas the same dose of orally administered (99m)Tc-hLF 1-11 induced about approximately 100 times reduction. In conclusion, intravenously and orally administrated (99m)Tc-hLF 1-11 accumulates in infected tissues and is highly effective against experimental infections with MRSA. Moreover, scintigraphy is an excellent tool to study the pharmacology of experimental compounds and to determine the uptake in infected tissues.
authors.affiliation: Department of Radiology, Section of Nuclear Medicine, Leiden University Medical Center (LUMC), Leiden, The Netherlands.
authors.forename: Carlo P J M
authors.initials: CP
authors.lastname: Brouwer
authors.forename: Mick M
authors.initials: MM
authors.lastname: Welling
mesh_terms: D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D006801:Humans; D007781:Lactoferrin; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011786:Quality Control; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D013203:Staphylococcal Infections / Q000000981:diagnostic imaging* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000302:isolation & purification / Q000378:metabolism; D013667:Technetium; D014018:Tissue Distribution
chemical_list: D023181:Antimicrobial Cationic Peptides; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C466658:lactoferrin (1-11), human; D013667:Technetium; D007781:Lactoferrin; D000409:Alanine