Identifying the targets that bacterial viruses, or phages, use to halt bacterial growth and then screening against those targets for small molecule inhibitors that attack the same targets provides a unique platform for the discovery of novel antibiotics. Researchers from Montreal-based PhageTech, Inc. describe in the February issue of Nature Biotechnology this novel method for discovering new classes of antibiotics. The article is available on-line today at www.nature.com/nbt/.
"Over the course of evolution, the multitudes of phages that attack bacteria have developed unique proteins that bind to and inactivate (or redirect) critical cellular targets within their prey," said Jing Liu, Ph.D., corresponding author of the publication. "This binding shuts off key metabolic processes in the bacteria, diverting those organisms from their own growth and reproduction to the production of new phage progeny. We believe these phage-identified bacterial "weak spots" will provide useful screening targets for discovering the sorts of truly novel antibiotics needed to combat growing antibiotic resistance."
The publications authors used a high-throughput phage genomics strategy to identify novel 31 novel polypeptide families that inhibit Staphylococcus aureus growth when expressed in the bacteria. Several of these were found to attack targets essential for bacterial DNA replication or transcription. They then employed the interaction between a prototypic phage peptide, ORF104 of phage 77, and its bacterial target, DnaI, to screen for small molecule inhibitors. Using this strategy, the researchers found several novel compounds that inhibited both bacterial growth and DNA synthesis.
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