The Sea's Arsenal Against Infections
A major therapeutic area for marine natural products is infection. Tor Haug, Ph.D., associate professor at the Norwegian College of Fishery Science, Tromso, has isolated novel antimicrobial peptides (AMPs) from the blood of the small spider crab Hyas araneus and the green sea urchin Strongylocentrotus droebachiensis. Some of these AMPs contain modified amino acids that may protect them from degradation.
“Antimicrobial peptides are a new class of drugs,” says Dr. Haug. “They have a broad spectrum of activity against fungi, bacteria, and viruses. Their target is the bacterial membrane. They cause rapid lysis of the microbe and only rarely induce resistance.” He added that in terrestrial sources, there is a high rate of rediscovery of antibiotic compounds, which means the rate of novel compound discovery has been going down. In marine resources, the reverse is true. Also, marine compounds often contain halogen atoms, which terrestrial compounds rarely do, and this in itself may confer novelty.
Inge Nilsen, Ph.D., of the Norwegian Institute of Fishery Science, Tromso, has also been looking at new antibacterial weapons from the sea. Lysozyme is an enzyme with potent antibacterial properties that is present in all body fluids. It has recently been discovered that bacteria, mainly gram negatives, produce specific lysozyme inhibitors that disable this natural defense mechanism.
Dr. Nilsen has found several novel lysozyme inhibitors among a range of marine bacteria and is now looking for molecules that could block them. These molecules would not, in themselves, be antibiotics but would have the power to restore lysozyme’s ability to kill bacteria.
Marine-derived enzymes have huge commercial potential. The director of the Norwegian Structural Biology Centre (NorStruct), Arne Smalas, Ph.D., described work with the cold-adapted enzymes. “The best approach is to do comparative studies,” stated Smalas. Therefore, 3-D structures of salmon versus bovine trypsin, cod versus human uracil DNA glycosylase and the same enzyme, as well as endonucleases from V. salmonicida versus V.cholerae have been compared. These studies have yielded important clues to the structural features that are linked to an enzyme’s temperature profile.
Geir Klinkenberg, Ph.D., head of the high-throughput screening facility, described ongoing bioprospecting work at the Norwegian University of Science and Technology. They are searching the bottom sediments and surface biolayer of the Trondheim fjord for polyunsaturated fatty acids from eukaryotic protists, carotenoids from colored bacteria, and antimicrobials from actinomycetes. In the latter, the discovery program has so far yielded 33 isolates with activity against resistant fungi and 100 with activity against multidrug resistant enterococci.
Of course, terrestrial actinomycetes are well-established as an antibiotic source. “We put a lot of effort into dereplicating at an early stage but we still find a lot of known compounds,” said Dr. Klinkenberg. However, three to six potentially interesting compounds have been identified, and 100 more isolates are being subjected to further characterization.