title: Efficacy of liposomal bismuth-ethanedithiol-loaded tobramycin after intratracheal administration in rats with pulmonary Pseudomonas aeruginosa infection.
abstract: We sought to investigate alterations in quorum-sensing signal molecule N-acyl homoserine lactone secretion and in the release of Pseudomonas aeruginosa virulence factors, as well as the in vivo antimicrobial activity of bismuth-ethanedithiol incorporated into a liposome-loaded tobramycin formulation (LipoBiEDT-TOB) administered to rats chronically infected with P. aeruginosa. The quorum-sensing signal molecule N-acyl homoserine lactone was monitored by using a biosensor organism. P. aeruginosa virulence factors were assessed spectrophotometrically. An agar beads model of chronic Pseudomonas lung infection in rats was used to evaluate the efficacy of the liposomal formulation in the reduction of bacterial count. The levels of active tobramycin in the lungs and the kidneys were evaluated by microbiological assay. LipoBiEDT-TOB was effective in disrupting both quorum-sensing signal molecules N-3-oxo-dodeccanoylhomoserine lactone and N-butanoylhomoserine lactone, as well as significantly (P < 0.05) reducing lipase, chitinase, and protease production. At 24 h after 3 treatments, the CFU counts in lungs of animals treated with LipoBiEDT-TOB were of 3 log(10) CFU/lung, comparated to 7.4 and 4.7 log(10) CFU/lung, respectively, in untreated lungs and in lungs treated with free antibiotic. The antibiotic concentration after the last dose of LipoBiEDT-TOB was 25.1 μg/lung, while no tobramycin was detected in the kidneys. As for the free antibiotic, we found 6.5 μg/kidney but could not detect any tobramycin in the lungs. Taken together, LipoBiEDT-TOB reduced the production of quorum-sensing molecules and virulence factors and could highly improve the management of chronic pulmonary infection in cystic fibrosis patients.
authors.affiliation: Novel Drug and Vaccine Delivery Systems Facility, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, ON, Canada.
authors.forename: Moayad
authors.initials: M
authors.lastname: Alhariri
authors.forename: Abdelwahab
authors.initials: A
authors.lastname: Omri
mesh_terms: D054742:Acyl-Butyrolactones / Q000037:antagonists & inhibitors / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D001729:Bismuth / Q000737:chemistry; D004339:Drug Compounding; D007668:Kidney / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry*; D008168:Lung / Q000187:drug effects* / Q000382:microbiology; D008623:Mercaptoethanol / Q000031:analogs & derivatives / Q000737:chemistry; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development; D053038:Quorum Sensing / Q000187:drug effects; D051381:Rats; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000382:microbiology; D014031:Tobramycin / Q000493:pharmacokinetics* / Q000494:pharmacology; D016896:Treatment Outcome; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D054742:Acyl-Butyrolactones; D000900:Anti-Bacterial Agents; D008081:Liposomes; D037521:Virulence Factors; D008623:Mercaptoethanol; C031854:1,2-ethanedithiol; D001729:Bismuth; D014031:Tobramycin