Nature Biotechnology
22, 185 - 191 (2004)
Published online: 11 January 2004; | doi:10.1038/nbt932
Antimicrobial drug discovery through bacteriophage genomicsJing Liu1, 5, Mohammed Dehbi1, 5, Greg Moeck1, 5, Francis Arhin1, Pascale Bauda1, Dominique Bergeron1, Mario Callejo1, Vincent Ferretti1, Nhuan Ha1, Tony Kwan1, John McCarty1, Ramakrishnan Srikumar1, Dan Williams1, Jinzi J Wu1, Philippe Gros2, Jerry Pelletier2
& Michael DuBow3, 41
PhageTech Inc., 7170 Frederick Banting, 2nd Floor, Ville Saint Laurent, Quebec, Canada, H4S 2A1. 2
Department of Biochemistry, 3655 Promenade Sir William Osler, McIntyre Medical Sciences Building, McGill University, Montreal, Quebec, Canada, H3G 1Y6. 3
Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Quebec, Canada, H3A 2B4. 4
Present address: Institut de Génétique et Microbiologie, Université Paris-Sud, Bâtiment 409, 91405 Orsay, France. 5
These authors contributed equally to this work.
Correspondence should be addressed to Jing Liu jliu@phagetech.comOver 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 DnaI, 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.
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