Anti-Clostridium difficile potential of tetramic acid derivatives from Pseudomonas aeruginosa quorum-sensing autoinducers.
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.
Ueda
Chihiro
C
Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Ohmorinishi, Ohtaku, Tokyo 143-8540, Japan.
Tateda
Kazuhiro
K
Horikawa
Manabu
M
Kimura
Soichiro
S
Ishii
Yoshikazu
Y
Nomura
Kaoru
K
Yamada
Kanako
K
Suematsu
Takashi
T
Inoue
Yasuhisa
Y
Ishiguro
Masaji
M
Miyairi
Shinichi
S
Yamaguchi
Keizo
K
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
D000900:Anti-Bacterial Agents; D007783:Lactones; D011760:Pyrrolidinones; C085113:Pseudomonas aeruginosa autoinducer; C009435:tetramic acid; D006714:Homoserine