Method for Discovering New Classes of Antibiotics

By 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, researchers hope to discover novel antibiotics. Their method was reported in the January 11, 2004, online edition of Nature Biotechnology.

The researchers used a high throughput phage genomics strategy to identify 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. The interaction between a prototype phage peptide, ORF104 or phage 77, and its bacterial target, Dnal, was then used to screen for small molecule inhibitors. This strategy has resulted in several compounds that inhibited both bacterial growth and DNA synthesis.

This strategy, say the researchers, offers several benefits. "First, the bacterial targets identified in this manner are evolutionarily validated as important to bacterial growth and potentially susceptible to inactivation by small molecule drugs. This allows us to quickly pinpoint the most promising antimicrobial targets from among thousands of possible candidates. Second, this approach provides a ready-to-use screening assay based on inhibition of interactions between a phage peptide and its bacterial target,” explained Jinzi J. Wu, M.D., Ph.D., vice president, R&D biology, PhageTech, Inc. (Montreal, Canada).

Eight novel antimicrobial targets have been identified, against which the company is screening chemical libraries and applying medicinal chemistry to further refine and evaluate those inhibitors.



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