TY - JOUR
T1 - Klebsiella oxytoca enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities
AU - Unterhauser, Katrin
AU - Pöltl, Lisa
AU - Schneditz, Georg
AU - Kienesberger, Sabine
AU - Glabonjat, Ronald A.
AU - Kitsera, Maksym
AU - Pletz, Jakob
AU - Josa-Prado, Fernando
AU - Dornisch, Elisabeth
AU - Lembacher-Fadum, Christian
AU - Roier, Sandro
AU - Gorkiewicz, Gregor
AU - Lucena, Daniel
AU - Barasoain, Isabel
AU - Kroutil, Wolfgang
AU - Wiedner, Marc
AU - Loizou, Joanna I.
AU - Breinbauer, Rolf
AU - Díaz, José Fernando
AU - Schild, Stefan
AU - Högenauer, Christoph
AU - Zechner, Ellen L.
PY - 2019/2/26
Y1 - 2019/2/26
N2 - Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca. Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells—a hallmark feature of AAHC—by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis.
AB - Establishing causal links between bacterial metabolites and human intestinal disease is a significant challenge. This study reveals the molecular basis of antibiotic-associated hemorrhagic colitis (AAHC) caused by intestinal resident Klebsiella oxytoca. Colitogenic strains produce the nonribosomal peptides tilivalline and tilimycin. Here, we verify that these enterotoxins are present in the human intestine during active colitis and determine their concentrations in a murine disease model. Although both toxins share a pyrrolobenzodiazepine structure, they have distinct molecular targets. Tilimycin acts as a genotoxin. Its interaction with DNA activates damage repair mechanisms in cultured cells and causes DNA strand breakage and an increased lesion burden in cecal enterocytes of colonized mice. In contrast, tilivalline binds tubulin and stabilizes microtubules leading to mitotic arrest. To our knowledge, this activity is unique for microbiota-derived metabolites of the human intestine. The capacity of both toxins to induce apoptosis in intestinal epithelial cells—a hallmark feature of AAHC—by independent modes of action, strengthens our proposal that these metabolites act collectively in the pathogenicity of colitis.
KW - Antibiotic-induced diarrhea
KW - DNA damage
KW - Dysbiosis
KW - Intestinal microbiota
KW - Tubulin inhibitor
KW - Klebsiella Infections/genetics
KW - Enterotoxins/biosynthesis
KW - Humans
KW - Intestines/microbiology
KW - Peptides/metabolism
KW - Epithelial Cells/microbiology
KW - Microtubules/drug effects
KW - Animals
KW - Host Microbial Interactions/genetics
KW - Enterocolitis, Pseudomembranous/genetics
KW - Benzodiazepinones/metabolism
KW - DNA Damage/drug effects
KW - Mice
KW - Klebsiella oxytoca/genetics
KW - Oxyquinoline/analogs & derivatives
UR - http://www.scopus.com/inward/record.url?scp=85062009992&partnerID=8YFLogxK
U2 - 10.1073/pnas.1819154116
DO - 10.1073/pnas.1819154116
M3 - Article
C2 - 30808763
AN - SCOPUS:85062009992
SN - 0027-8424
VL - 116
SP - 3774
EP - 3783
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 9
ER -