Bacteriophage genomics approach to antimicrobial drug discoveryPublished On: Sun, Jan 11th, 2004 | Genomics | By BioNews
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 publication’s 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.
“This strategy offers several benefits as a novel approach to antimicrobial drug discovery,” said Jinzi J. Wu, M.D., Ph.D., PhageTech vice president, R&D – biology. “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 anti-microbial 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.”
“The fight against growing bacterial resistance requires new classes of antibiotics against novel targets. Our strategy of screening for compounds that address the same antibacterial targets attacked by phages is a very good way of identifying novel compounds against many different bacterial species,” concluded Dr Wu.
Applying its novel antibiotic discovery platform, PhageTech has identified eight novel antimicrobial targets against which the company is screening chemical libraries and applying medicinal chemistry to further refine and evaluate those inhibitors. PhageTech has also continued to expand its phage genomics platform from Staphylococcus aureus to other bacterial pathogens including Streptococcus pneumoniae and Pseudomonas aeruginosa.