A tricyclic pyrrolobenzodiazepine produced by Klebsiella oxytoca is associated with cytotoxicity in antibiotic-associated hemorrhagic colitis.

Autor: Tse H; From the Department of Microbiology.; Research Centre of Infection and Immunity, and.; the State Key Laboratory of Emerging Infectious Diseases, Hong Kong SAR, Hong Kong, China.; the Carol Yu Centre for Infection., Gu Q; Departments of Chemistry and., Sze KH; From the Department of Microbiology.; Research Centre of Infection and Immunity, and.; the State Key Laboratory of Emerging Infectious Diseases, Hong Kong SAR, Hong Kong, China.; the Carol Yu Centre for Infection., Chu IK; Departments of Chemistry and., Kao RY; From the Department of Microbiology.; Research Centre of Infection and Immunity, and.; the State Key Laboratory of Emerging Infectious Diseases, Hong Kong SAR, Hong Kong, China.; the Carol Yu Centre for Infection., Lee KC; From the Department of Microbiology.; Research Centre of Infection and Immunity, and.; the State Key Laboratory of Emerging Infectious Diseases, Hong Kong SAR, Hong Kong, China.; the Carol Yu Centre for Infection., Lam CW; Pathology, the University of Hong Kong and., Yang D; Departments of Chemistry and., Tai SS; Departments of Chemistry and., Ke Y; From the Department of Microbiology., Chan E; From the Department of Microbiology., Chan WM; From the Department of Microbiology., Dai J; From the Department of Microbiology., Leung SP; From the Department of Microbiology., Leung SY; Pathology, the University of Hong Kong and., Yuen KY; From the Department of Microbiology, kyyuen@hku.hk.; Research Centre of Infection and Immunity, and.; the State Key Laboratory of Emerging Infectious Diseases, Hong Kong SAR, Hong Kong, China.; the Carol Yu Centre for Infection.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2017 Nov 24; Vol. 292 (47), pp. 19503-19520. Date of Electronic Publication: 2017 Sep 26.
DOI: 10.1074/jbc.M117.791558
Abstrakt: Cytotoxin-producing Klebsiella oxytoca is the causative agent of antibiotic-associated hemorrhagic colitis (AAHC). Recently, the cytotoxin associated with AAHC was identified as tilivalline, a known pentacyclic pyrrolobenzodiazepine (PBD) metabolite produced by K. oxytoca Although this assertion of tilivalline's role in AAHC is supported by evidence from animal experiments, some key aspects of this finding appear to be incompatible with toxicity mechanisms of known PBD toxins. We therefore hypothesized that K. oxytoca may produce some other uncharacterized cytotoxins. To address this question, we investigated whether tilivalline alone is indeed necessary and sufficient to induce cytotoxicity or whether K. oxytoca also produces other cytotoxins. LC-MS- and NMR-based metabolomic analyses revealed the presence of an abundant tricyclic PBD, provisionally designated kleboxymycin, in the supernatant of toxigenic K. oxytoca strains. Moreover, by generating multiple mutants with gene deletions affecting tilivalline biosynthesis, we show that a tryptophanase-deficient, tilivalline-negative K. oxytoca mutant induced cytotoxicity in vitro similar to tilivalline-positive K. oxytoca strains. Furthermore, synthetic kleboxymycin exhibited greater than 9-fold higher cytotoxicity than tilivalline in TC 50 cell culture assays. We also found that the biosynthetic pathways for kleboxymycin and tilivalline appear to overlap, as tilivalline is an indole derivative of kleboxymycin. In summary, our results indicate that tilivalline is not essential for inducing cytotoxicity observed in K. oxytoca -associated AAHC and that kleboxymycin is a tilivalline-related bacterial metabolite with even higher cytotoxicity.
(© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
Databáze: MEDLINE
Externí odkaz: