Shedding light on killer islands

By Susan Gammon, Ph.D.
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Not all islands are exotic vacation spots.  Some islands, “pathogenicity islands,” are genetic elements found in bacteria that make you sick. These islands convey virulence factors to bacteria, and in the case of Bacteroides fragilis, can cause inflammatory diarrhea, ulcerative colitis, and increase the risk of colorectal cancer.

In a new study, researchers at Sanford-Burnham, led by Alex Strongin, Ph.D., professor in the Infectious and Inflammatory Disease Center, and Igor Kozlov, Ph.D., of Prognosys Biosciences, performed a full characterization of metalloproteinase II (MPII), a key protease encoded on the pathogenicity island of the B. fragilis genome.

The study revealed that MPII has a “dibasic” cleavage preference—meaning it likes to “cut” proteins at the point between two basic amino acids.  It also showed that B. fragilis requires both MPII and fragilysin (FRA)—also a metalloproteinase—to carry out its pathogenic antics.

MPII and FRA reside together on the pathogenicity island of toxic B. fragilis strains. The proteases are thought to “remodel” the normal luminal epithelium of the gastrointestinal tract, paving the way for inflammation and disease by disrupting membrane structure and function.

“Until now, the biochemical characteristics of MPII were completely unknown. Our study, defining the specificity of MPII, is a necessary first step in developing drugs to inhibit the enzyme,” Strongin said. “Knowing the optimal peptide substrates can make the subsequent steps in drug development go much faster, and in some cases, provide a drug lead that is a few steps from a drug.”

B. fragilis is the most frequent gastrointestinal disease-causing anaerobic bacteria. Anaerobic—meaning “life without air”—bacteria can cause an infection when a normal healthy barrier, such as skin, gums, or intestinal walls, is damaged due to surgery, injury, or disease. If the immune system doesn’t tackle invading bacteria, these anaerobes will thrive in low-oxygen environments. Although it constitutes 1 to 2 percent of normal gut flora, B. fragilis accounts for over 80 percent of anaerobic infections.

Other authors of the paper include Sergey Shiryaev, Albert Remacle, Andrei  Chernov, Vladislav Golubkov, and Khatereh Motamedchaboki from the Strongin lab, and Piotr Cieplak of Prognosis Biosciences.

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Susan Gammon, Ph.D.

Susan is an associate director of Communications at Sanford-Burnham.

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