Endosymbiotic by nature

You might remember endosymbiotic theory from your high school or college biology classes: it’s the idea that some organelles (for example, mitochondria and chloroplasts) were originally separate prokaryotic organisms that were engulfed by eukaryotic cells. Although it’s not clear how or why this occurred, this became a mutually beneficial relationship for both cells (i.e., a symbiotic relationship), resulting in the organelle-containing cells that appear in biology textbooks (and in our bodies…)

But why – you might ask – would a chemist care about endosymbionts (organisms that live inside other organisms)? Well I think they’re interesting because “”http://www.pnas.org/cgi/content/abstract/101/46/16222">[b]acterial symbionts have long been suspected to be the true producers of many drug candidates" isolated from natural sources. For example, there is some evidence that the antitumor polyketides of the pederin family are produced by an uncultured bacterial symbiont of Paederus beetles, which can cause dermatitis.

Late last year, Partida-Martinez & Hertweck discovered that another natural product (rhizoxin) is not biosynthesized by the fungus Rhizopus microsporus itself, but by a bacteria that lives inside the fungus. In a follow-up paper in JACS, these authors were able to isolate a rhizoxin-producing bacterial strain from the fungus (“Burkholderia rhizoxina”) and could grow it in liquid culture. They lysed the cells, and found (quite surprisingly) that “about 40% of the crude extract is composed of rhizoxin derivatives” – in addition to rhizoxin, Burkholderia rhizoxina produces a number of related structures.

The authors determined that some of these natural products were 1,000 to 10,000 times more active than rhizoxin in cell-based assays (the assay was looking at antiproliferative activity). Rhizoxin went through extensive clinical trials in the 1990s and showed some promise as an anti-cancer drug, though it was not taken into Phase III clinical trials because it was not active enough in vivo. These authors hope that, since the derivatives they isolated are more active in vitro, they might more successful in the clinic. And since the natural products can be harvested from bacterial cultures, it may be possible to rapidly produce a large amount of these complex natural products without having to resort to chemical synthesis.


Joshua Finkelstein (Associate Editor, Nature)