reductase enzymes that allow H. pylori to break down organic nitrogen compounds. The enzyme also happens to convert metronidazole to hydroxylamine, which damages DNA, proteins and other macromolecules and kills the bacterium. So the bacterium changes a harmless chemical into a lethal drug. When the rdxA gene is inactivated by mutation, however, H. pylori can?t break down metronidazole and therefore becomes resistant.

 After the Dalhousie scientists cloned and sequenced rdxA, they and their Washington University collaborators showed that this gene is responsible for resistance. First, the researchers found that the bacterium E. coli, which normally is metronidazole-resistant, became sensitive to the drug when they inserted rdxA from H. pylori into it. Second, they made resistant H. pylori sensitive again by adding extra copies of rdxA.

They also specifically inactivated rdxA in H. pylori simply by inserting another marker gene into it, thereby disrupting its DNA sequence. The H. pylori with the mutant rdxA gene became fully metronidazole-resistant. This critical experiment showed that rdxA alone confers metronidazole sensitivity and that its loss of function is sufficient to cause resistance. "It was very satisfying to see that the altered strains, whose only difference from the wild type was having this inactivated gene, showed metronidazole resistance," says Douglas E. Berg, Ph.D., the Alumni Professor in Molecular Microbiology and professor of genetics at Washington University School of Medicine in St. Louis.

Berg and research associate Dangeruta Kersulyte, Ph.D., also looked to see whether normally sensitive H. pylori strains become etronidazole-resistant by picking up mutant genes from already resistant strains -- many bacteria donate pieces of DNA that carry resistance genes to other strains or species. The researchers therefore examined pairs of H. pylori isolates from patients in Peru and Lithuania, where infection rates
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Contact: Linda Sage
sage@medicine.WUSTL.edu
314-432-8566
Washington University School of Medicine
15-Apr-1998

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