Antimicrobial drug discovery through bacteriophage genomics

Jing Liu, Mohammed Dehbi, Greg Moeck, Francis Arhin, Pascale Banda, Dominique Bergeron, Mario Callejo, Vincent Ferretti, Nhuan Ha, Tony Kwan, John McCarty, Ramakrishnan Srikumar, Dan Williams, Jinzi J. Wu, Philippe Gros, Jerry Pelletier, Michael DuBow

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158 Citations (Scopus)

Abstract

Over evolutionary time bacteriophages have developed unique proteins that arrest critical cellular processes to commit bacterial host metabolism to phage reproduction. Here, we apply this concept of phage-mediated bacterial growth inhibition to antibiotic discovery. We sequenced 26 Staphylococcus aureus phages and identified 31 novel polypeptide families that inhibited growth upon expression in S. aureus. The cellular targets for some of these polypeptides were identified and several were shown to be essential components of the host DNA replication and transcription machineries. The interaction between a prototypic pair, ORF104 of phage 77 and Dnal, the putative helicase loader of S. aureus, was then used to screen for small molecule inhibitors. Several compounds were subsequently found to inhibit both bacterial growth and DNA synthesis. Our results suggest that mimicking the growth-inhibitory effect of phage polypeptides by a chemical compound, coupled with the plethora of phages on earth, will yield new antibiotics to combat infectious diseases.

Original languageEnglish
Pages (from-to)185-191
Number of pages7
JournalNature Biotechnology
Volume22
Issue number2
DOIs
Publication statusPublished - Feb 2004

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ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Molecular Medicine
  • Biomedical Engineering

Cite this

Liu, J., Dehbi, M., Moeck, G., Arhin, F., Banda, P., Bergeron, D., Callejo, M., Ferretti, V., Ha, N., Kwan, T., McCarty, J., Srikumar, R., Williams, D., Wu, J. J., Gros, P., Pelletier, J., & DuBow, M. (2004). Antimicrobial drug discovery through bacteriophage genomics. Nature Biotechnology, 22(2), 185-191. https://doi.org/10.1038/nbt932