MADISON – November 22, 2005 – Researchers from Washington University Medical School in St. Louis and NimbleGen Systems have identified evolutionary changes in the human pathogen Helicobacter pylori as it develops resistance to antibiotics, according to a study published online in Nature Methods ¹.

Mutations that adapted H. pylori to increasing levels of metronidazole were rapidly identified in nearly a dozen, serially adapted, antibiotic-resistant strains. H. pylori, recently in the news after two Australian scientists were awarded the Nobel Prize for the discovery of this bacterium, is implicated in peptic ulcer disease and gastric cancers.

To pinpoint the mutations, researchers used a novel method developed at NimbleGen, termed Comparative Genome Sequencing (CGS), which can find a single point change in millions of bases of DNA with nearly perfect accuracy. The characterization of H. pylori strains in this study represents the equivalent of sequencing 3.3 million bases of DNA and identifying 11 confirmed mutations without error. This scale of genomic characterization was achieved in a matter of weeks and cost roughly 80% less than conventional or high-throughput DNA sequencing methods.

“I’m eager to continue these studies, looking at evolutionary changes as H. pylori strains adapt to further antibiotic pressure, or adapt to host inflammatory and other defense responses and thereby persist for decades,” said Dr. Douglas Berg, lead researcher on the project and professor of molecular microbiology, genetics and medicine at Washington University Medical School. “This approach provides us with a model for understanding adaptations that are important in pathogen evolution, human infection and disease.”

The CGS technique provides the ability to compare entire microbial genomes for the purpose of strain identification, characterization of genomic changes in response to environmental forces, and the optimization of industrially important microbes. It can help trace movement of specific pathogens in human, animal or plant populations and provide important insights into how microbes adapt to different environments—findings that will be increasingly important for public health and epidemiology, bioremediation, industrial fermentation and biosynthetic strain optimization, and vaccine development. CGS is a two-step process that leverages the flexibility of NimbleGen’s high-density DNA microarrays. The first step involves using a set of custom arrays to identify all DNA copy number changes (insertions, deletions, amplifications, point mutations) in microbial genomes. The second step involves custom design of arrays to re-sequence all affected regions and fully characterize all SNPs.

1 This research resulted in the December Nature Methods publication “ Mutation discovery in bacterial genomes: metronidazole resistance in Helicobacter pylori” (Albert, TA, et al. (2005) Nature Methods 2: 951-953.).

This document (doi:10:1038) may be viewed online at http://www.nature.com/nmeth/journal/v2/n12/index.html.

Authors of this study were Thomas J. Albert, Jason E. Norton, Todd A. Richmond, Michael Molla, Jaz Singh, and Roland Green (NimbleGen Systems, Madison, WI); Daiva Dailidiene, Giedrius Dailide, and Douglas E. Berg, (Departments of Molecular Microbiology, Genetics, and Medicine, Washington University Medical School, St. Louis, MO); and Awdhesh Kalia (Department of Biology, and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY).

NimbleGen Systems Inc.