Antimicrobial drug discovery through bacteriophage genomics
| Autor: | John S. McCarty, Mohammed Dehbi, Greg Moeck, Tony Kwan, Daniel M. Williams, Jerry Pelletier, Vincent Ferretti, Mario Callejo, Francis F. Arhin, Ramakrishnan Srikumar, Michael S. DuBow, Philippe Gros, Pascale Bauda, Jinzi J Wu, Nhuan Ha, Dominique Bergeron, Jing Liu |
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| Rok vydání: | 2004 |
| Předmět: |
biology
medicine.drug_class Antibiotics Biomedical Engineering DNA replication dnaI Helicase Bioengineering Genomics medicine.disease_cause biology.organism_classification Applied Microbiology and Biotechnology Genome Microbiology Bacteriophage Staphylococcus aureus medicine biology.protein Molecular Medicine Biotechnology |
| Zdroj: | Nature Biotechnology. 22:185-191 |
| ISSN: | 1546-1696 1087-0156 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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