Editor's Note: Science Scan is a roundup of recently published biotechnology-relevant research.
What the world of medical practice needs is an antibiotic that doesn't provoke resistance in bacteria and can be produced in the lab. A key word in that direction is "lantibiotic," a compound that has been widely used as a food preservative without inducing bacterial resistance. But researchers haven't been able to synthesize new variations of those promising peptides. Much of the difficulty relates to the fact that lantibiotics are compounded in two hard-to-make stages: After the compounds come off the cell's peptide assembly line, additional enzymes tinker with the molecules to generate their mature forms. Chemists at the University of Illinois at Urbana-Champaign studied lantibiotic lacticin 481.
They reported that the entire series of modifications in that second stage is catalyzed by a single enzyme called LctM. That chemical turns out to be flexible in the sort of modifications it's willing to carry out. The authors suggested that it might offer an excellent system for engineering new variations of lacticin. They have uncovered the molecular activity of an enzyme responsible for naturally turning a small protein into a potent antibiotic - that is, a lantibiotic.
They describe their finding in the Jan. 30, 2004, issue of Science. It's titled: "Lacticin 481: In vitro reconstitution of lantibiotic synthetase activity."
"Our discovery unlocks a door that could lead to a new line of antibiotic compounds based on nature's machinery," said Willfred van der Donk, a professor of chemistry at the university and senior author of the article. Their work was done using lacticin 481, a lantibiotic generated by one of several strains of Lactococcus lactis, a bacterium used in cheese production.
Variants serve to preserve other dairy products and canned vegetables. "The lantibiotic risin has been in use for more than 50 years," van der Donk told BioWorld Today, "as an alternative to chemicals in food preservation in more than 40 countries without the development of significant antibiotic resistance. The use of antibiotics is an important area of medicine," he added, "because pathogenic bacteria are always in the environment. It's important to renew our arsenal of compounds that combat pathogens. With the development of bacterial resistance," van der Donk continued, "- not just the kind that occurs through evolution, but the kind potentially created in biological weapons by terrorists - we will always need new antibiotics."
The Science paper leads off by explaining that "the lantibiotic lacticin 481 is synthesized on ribosomes as a pre-peptide [LctA] and post-translationally modified to its mature form. These modifications include dehydration of serines and threonines, followed by intramolecular addition of cysteines to the unsaturated amino acids, which generate cyclic thioethers. We have characterized the in vitro activity of LctM, which completely processed a series of LctA mutants, displaying a permissive substrate specificity that holds promise for antibiotic engineering."
Chemical Mixture of Zinc, Copper Helpful In Alzheimer's Disease, Also Likely In Parkinson's
A rear-view mirror image of the preceding item is a report in the Archives of Neurology. Its title: "Metal-protein attenuation with iodochlorhydroxyquin [Clioquinol] targeting Ab amyloid deposition and toxicity in Alzheimer's disease. A pilot phase 2 clinical trial." The journal article is dated December 2003.
The clinical study, led by researchers from the University of Melbourne in Australia, finds that treatment with an antibiotic that also removes zinc and copper from tissue might benefit patients with Alzheimer's disease (AD). The results suggest that the medication, called clioquinol, might inhibit the accumulation of amyloid plaques in the brains of AD patients. Participants in the pilot study, all with moderate disease, who received the drug showed less cognitive decline than did AD control participants. The approach to a potential AD treatment was developed by researchers at Massachusetts General Hospital, who are co-authors of the paper.
The Melbourne team sought to determine whether clinquinol - a metal-protein attenuating compound (MPAC) might help to reduce beta-amyloid levels and slow the rate of cognitive decline in patients with AD. They surmise that the compound works by inhibiting zinc and copper ions from binding to beta-amyloid, thereby helping to dissolve the protein and preventing it from accumulating
The researchers conducted a pilot Phase II trial of their chelation therapy in 36 patients with moderately severe AD. Eighteen patients received 125 milligrams of clinquinol twice daily for 12 weeks, then 250 milligrams twice a day for weeks 13 to 24 and 375 milligrams from weeks 25 to 36. The patients were given tests to measure cognition at the beginning of the study and again at weeks four, 12, 24 and 36.
The co-authors reported that "plasma beta-amyloid levels declined in the clinquinol group and increased in the placebo contingent. Patients taking clinquinol had better cognitive scores. The findings support a proof of concept in humans," the co-authors write, "that a drug targeting metal/beta-amyloid interactions can have a significant effect on beta-amyloid metabolism, and through this, a beneficial modification on the progression of AD.
"The safety profile and the biochemical efficacy of clinquinol in this population are sufficiently encouraging to allow for future trials to take this investigation [clioquinol itself or a pharmacologically-improved backup] targeting beta-amyloid to the next phase. This class of MPAC," they added, "may also be considered for related conditions, such as Parkinson's disease."
If Human Osteoporosis Mimics Mouse Model, Its Inhibitors May Treat Lifestyle Bone/Mineral Disease
Researchers have combined classic mouse genetics with genomics and pharmacology. They discovered that a gene, Alox15, improves bone mineral density. The risk of incurring osteoporosis is influenced by well-understood lifestyle factors - unlike variations about bone and mineral density in which little is known.
The journal article in Science dated Jan. 9, 2004, is titled "Regulation of bone mass in mice by the lipoxygenase gene Alox15." The lead author, Robert Klein, and his co-authors determined that mice lacking Alox15 had greater bone density than normal mice. If the human counterpart of Alox15, they conclude, plays the same role, then such inhibitors might be useful for treating the disorder.