Leuven researchers discover potential anti-cancer agents in diseased fish
A research team led by prof. Joleen Masschelein from the VIB – KU Leuven Center for Microbiology and the Department of Biology at KU Leuven, has discovered new potential anti-cancer agents. These substances are produced by Pseudomonas baetica, a bacterium that was isolated from the liver of a diseased flatfish. The results have been published in the prestigious journal Angewandte Chemie.
Oximidines in diseased fish
In March 2006, a mysterious disease swept through a Spanish population of cultured wedge soles – a species of flatfish popular for human consumption. To pinpoint the responsible pathogen(s), researchers performed detailed genetic analyses. Their investigations identified several species of Pseudomonas bacteria in the liver of the fish as the likely culprits, including a new strain called Pseudomonas baetica. Further examination of these Pseudomonas bacteria by the research team of prof. Joleen Masschelein has now revealed genes in the DNA that are responsible for constructing a group of anticancer agents, called oximidines.
Oximidines can selectively inhibit the function of mammalian V-ATPases, proton pumps that control the pH balance within cells. The malfunctioning of these pumps is associated with a range of human diseases, including neurodegeneration, osteoporosis, and cancer. In total, the team discovered three novel oximidine variants that all show potent anticancer activity.
"To our surprise, we discovered that the same bacterium that caused the mysterious disease in the soles is able to produce anti-cancer compounds." - Prof. Joleen Masschelein
Bio-engineering future medicines?
Following this discovery, the team of prof. Masschelein went a few steps further. First, they elucidated the pathway that the bacteria use to assemble these oximidines. What they found was unique. The three novel oximidines are produced by a molecular assembly line that installs a rare O-methyloxime group in a way that has never been seen before in bacteria.
Since the early 2000s, chemists have attempted to synthesize the oximidines and novel structural variants from scratch through chemical synthesis. However, the structural complexity of the oximidines made this a challenging, time-consuming and expensive process. The discovery of the oximidine genes in the Pseudomonas bacteria now paves the way for the more sustainable, environmentally-friendly and efficient production of novel oximidine variants with improved pharmacological properties.
As a proof of concept, the researchers used bio-engineering to edit the DNA of the bacteria and manipulate this unique assembly line. As a result, they were able to make the bacteria produce a structurally simpler oximidine that is more stable than its natural, complex counterparts, but still has the same strong anticancer activity.
"By manipulating this unique assembly line in the bacteria, we were able to create a structurally simpler oximidine that still maintains its strong anticancer activity. These findings open up new avenues for the bioengineering of novel oximidine analogues that could help fight cancer and other diseases." - Prof. Joleen Masschelein
While this discovery sounds promising for cancer research, much more research will be needed to further explore the potential of bioengineered oximidines in actual treatments for cancer or other diseases.