Antimicrobial drug discovery through bacteriophage genomics

Nat Biotechnol. 2004 Feb;22(2):185-91. doi: 10.1038/nbt932. Epub 2004 Jan 11.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / therapeutic use
  • Bacterial Infections / drug therapy
  • Bacterial Infections / metabolism
  • Bacterial Infections / virology
  • Bacterial Proteins / metabolism*
  • Bacteriophages / metabolism
  • Drug Delivery Systems / methods*
  • Drug Design
  • Gene Expression Profiling / methods
  • Genome, Viral
  • Humans
  • Proteome / metabolism*
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / metabolism
  • Staphylococcal Infections / virology
  • Staphylococcus Phages / metabolism*
  • Staphylococcus aureus / metabolism*
  • Staphylococcus aureus / virology*
  • Viral Proteins / metabolism*

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Proteome
  • Viral Proteins