title: Anti-Clostridium difficile potential of tetramic acid derivatives from Pseudomonas aeruginosa quorum-sensing autoinducers.
abstract: We have examined the potential bactericidal activities of several tetramic acids derived from Pseudomonas autoinducers against Clostridium difficile, a cause of antibiotic-associated pseudomembranous colitis. Clinical isolates of C. difficile (n=4) were incubated in broth with a chemically synthesized Pseudomonas autoinducer and its tetramic acid derivatives. The structure-activity relationship and the mechanisms of action were examined by a time-killing assay and by determination of the morphological/staining characteristics. The use of some tetramic acids derived from N-3-oxododecanoyl L-homoserine lactone resulted in more than 3-log reductions in the viability of C. difficile within 30 min at 30 microM. The outer membrane was suggested to be one of the targets for the bactericidal activity of tetramic acid, because disturbance of the bacterial outer surface was demonstrated by alteration of the Gram-staining characteristic and electron microscopy. The data for the tetramic acid derivatives demonstrate that the keto-enol structure and the length of the acyl side chain of tetramic acid may be essential for the antibacterial activity of this molecule. These results suggest the potential for tetramic acid derivatives to be novel agents with activity against C. difficile.
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ueda
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tateda
authors.forename: Manabu
authors.initials: M
authors.lastname: Horikawa
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kimura
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ishii
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nomura
authors.forename: Kanako
authors.initials: K
authors.lastname: Yamada
authors.forename: Takashi
authors.initials: T
authors.lastname: Suematsu
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Inoue
authors.forename: Masaji
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyairi
authors.forename: Keizo
authors.initials: K
authors.lastname: Yamaguchi
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects* / Q000648:ultrastructure; D006714:Homoserine / Q000031:analogs & derivatives* / Q000737:chemistry; D007783:Lactones / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D046529:Microscopy, Electron, Transmission; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053038:Quorum Sensing / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents; D007783:Lactones; D011760:Pyrrolidinones; C085113:Pseudomonas aeruginosa autoinducer; C009435:tetramic acid; D006714:Homoserine