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Barberry: Plant May Hold Key To Ultimate Antibiotic

by Mairin Brennan

A compound isolated from plants used in traditional Native American medicine may prove a key discovery for the development of drugs to treat antibiotic-resistant bacteria, including "super bugs" resistant to multiple drugs [Proc. Natl. Acad. Sci. USA, 97,1433 (2000)].

Kim Lewis, professor of biotechnology at Tufts University Biotechnology Center, Medford, Mass., and Frank R. Stermitz, professor of chemistry at Colorado State University, Fort Collins, and coworkers isolated 5'-methoxyhydnocarpin (5'-MHC) from the leaves of barberry plants. Coupled with antibiotics, the compound inactivates strains of Staphylococcus aureusthat are largely responsible for staph infections contracted in hospitals.

The discovery validates the philosophy of the two-pronged approach toward developing antibacterial drugs, notes Leo Grinius, a senior scientist in drug development for infectious diseases at Procter & Gamble. In this approach, a compound that undermines the bacterium's defense mechanism is combined with one that kills it. So far, though, only one such agent (an amoxicillin-clavulanic acid combination) is on the market, he notes. Medicinal plants adopted the two-pronged strategy during their evolution, and they "are ahead of us" in devising ways to protect against pathogens, he suggests.

A seemingly paradoxical behavior of barberry plants, which secrete the antibiotic berberine, led to the isolation of 5'-MHC. Berberine "is not very effective against microbial pathogens," Lewis says, "because the microbes simply pump the antibiotic out of their cells. So we have an interesting situation: The plant is making an antibiotic that is [apparently] ineffective, because virtually all bacteria, yeast, and other pathogens have pumps to pump it out." Yet some protective mechanism must be operating in barberry plants, because they are not known to be infected by bacterial pathogens.

Lewis reasoned the plants must make an inhibitor that jams an invading pathogen's pump, allowing berberine to enter the cell and kill it. He hypothesized that such an inhibitor might disable the "multidrug" resistance pumps" that render antibiotics ineffective against bacteria resistant to multiple drugs. These pumps are transmembrane proteins that eject the antibiotics from the organisms. The team isolated 5'-MHC, which indeed inhibits such pumps.

By itself, 5'-MHC has no antimicrobial activity, the team showed. But it acts synergistically with berberine and a number of other antibiotics to inactivate the strain of S. aureus that's resistant to antiseptics and quinolone-based antibiotics such as norfloxacin. 5'-MHC disables the strain's resistance-conferring pump, allowing antibiotics to accumulate in the bacterium and kill it. The researchers have also found the same synergistic effect with 5'-MHC in combination with the wide-spectrum antibiotic ciprofloxacin, Lewis says.

Synergy is a popular concept in the field of herbal medicine, Stermitz notes, and "our study shows for the first time at the molecular level that it is not a fantasy." He suggests that frequent failures to isolate active ingredients from medicinal plants may be due to researchers targeting only one compound, which, without its synergistic partner, is inactive.

The Tufts-CSU discovery "has unlocked the door to more effective use of antibiotics without having to resort to substances of higher potency" and the consequences they can impose--increased risk, toxicity, and more virulent pathogens, notes Manuel Aregullin, director of the Laboratory of Phytochemistry & Plant-Animal Interaction at Cornell University. "The findings show we have not exhausted the potential of nature in yielding medicinally useful chemicals," he says.

SOURCE: The Educational Technology Center - Northeastern University (edtech.neu.edu)

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Barberry: Plant May Hold Key To Ultimate Antibiotic