Some bacteria are
sensitive to penicillin, others are not. While patients swallow antibiotics to
destroy harmful microorganisms, their own intestinal microbiota suffers
changes. If the introduced unbalance leads to an overgrowth of bacteria
producing toxins themselves, intestinal and metabolic disorders can follow. In
an interdisciplinary collaboration, Ellen Zechner of the University of Graz,
Austria, and her colleagues have researched the role of
penicillin-resistant Klebsiella oxytoca enterobacterium in
antibiotic-associated hemorrhagic colitis (AAHC).
They first
identified a metabolite tilivalline as a critical enterotoxin, which in higher
doses damages the intestinal epithelium and can induce colitis. Surprisingly,
tilivalline shares its chemical structure with a class of soil bacteria
metabolites called pyrrolobenzodiazepines, which are already investigated and
applied in clinical trials for their antitumor properties. After having
identified the gene cluster for tilivalline synthesis, the scientists performed
comprehensive biomolecular and molecular genetic experiments to track down the
complete biosynthetic pathway of tilivalline.
Tilivalline itself
lacks the DNA-damaging activity of its antitumor antibiotic relatives because
the chemical site crucial for DNA interference is blocked. However, Zechner and
colleagues found that the source of the blocking, an indole, only enters the
biosynthetic pathway at its end. The tilivalline precursor without the indole,
which was then named tilimycin, was shown to be a more potent cytotoxin than
tilivalline. Surprisingly, the final addition of the indole to tilimycin occurs
spontaneously, without the help of any enzyme. This means that "Klebsiella
oxytoca is able to produce two pyrrolobenzodiazepines with distinct
functionalities depending on the availability of indole," the scientists
stated. Indole occurs naturally in the human gut.
Both outcomes, the
elucidation of the biosynthetic pathway and the discovery of tilimycin as a
stable intermediate metabolite, which is even more toxic to human cells, have
important physiological and pharmacological implications. First, the better
understanding of the AAHC pathogenesis may lead to new treatment schemes and
strategies to avoid or just alleviate antibiotic side reactions. And second,
the unusual Klebsiella pathway to the anticancerogenic structures can inspire
scientists to develop new approaches for producing anticancer drugs.
See:
Posted by Dr. Tim Sandle