title: In vitro microbiological characterization of a novel azalide, two triamilides and an azalide ketal against bovine and porcine respiratory pathogens.
abstract: Several novel 15-membered-ring macrolide agents (azalide 1, triamilides 2 and 3, and the azalide 3,6-ketal 4) were identified as potential antibacterial agents against Mannheimia (formerly named as Pasteurella) haemolytica, Pasteurella multocida, Haemophilus somnus and Actinobacillus pleuropneumoniae, important etiological agents of bovine and porcine respiratory disease. Compound 3 is the major component of the antibiotic tulathromycin. Antibacterial activity against tilmicosin-resistant P. multocida field isolates was also tested. In vitro MIC 50/90 analysis revealed that the four newly synthesized compounds were more potent than tilmicosin against M. haemolytica (4 to approximately 8x), P. multocida (8 to approximately 16x), A. pleuropneumoniae (4x), H. somnus (2x and 16x), and tilmicosin-resistant P. multocida (32x). In time-kill kinetic studies, all four novel compounds and tilmicosin showed bactericidal activity against M. haemolytica, P. multocida and A. pleuropneumoniae at both 4x and 8x MIC. A functional assay using genetically defined mutants revealed that all four novel compounds were poorer substrates for the efflux pump, AcrA/B system, than tilmicosin. A pH study using LPS mutants indicated that the enhanced in vitro potency of the triamilides, particularly compound 3 was mainly due to better penetration of the molecule through the outer membrane. The third amine group at the C-4'' position of the triamilde molecules contributed to this increased membrane penetration by increasing overall basicity. These studies indicate that the four novel compounds have potential as antibacterial agents against bovine and porcine respiratory disease.
authors.affiliation: Pfizer Global Research & Development, Pfizer Inc, Groton, CT 06340, USA.
authors.forename: Laura J L
authors.initials: LJ
authors.lastname: Norcia
authors.forename: Annette M
authors.initials: AM
authors.lastname: Silvia
authors.forename: Sheryl L
authors.initials: SL
authors.lastname: Santoro
authors.forename: Jim
authors.initials: J
authors.lastname: Retsema
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.forename: Brian S
authors.initials: BS
authors.lastname: Bronk
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Lundy
authors.forename: Bingwei
authors.initials: B
authors.lastname: Yang
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Evans
authors.forename: Shigeru F
authors.initials: SF
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002417:Cattle; D002418:Cattle Diseases / Q000382:microbiology; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D007700:Kinetics; D018942:Macrolides / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D013552:Swine; D013553:Swine Diseases / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D011500:Protein Synthesis Inhibitors