Antimicrobial drug discovery through bacteriophage genomics.
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.
Liu
Jing
J
PhageTech Inc., 7170 Frederick Banting, 2nd Floor, Ville Saint Laurent, Quebec, Canada, H4S 2A1. jliu@phagetech.com
Dehbi
Mohammed
M
Moeck
Greg
G
Arhin
Francis
F
Bauda
Pascale
P
Bergeron
Dominique
D
Callejo
Mario
M
Ferretti
Vincent
V
Ha
Nhuan
N
Kwan
Tony
T
McCarty
John
J
Srikumar
Ramakrishnan
R
Williams
Dan
D
Wu
Jinzi J
JJ
Gros
Philippe
P
Pelletier
Jerry
J
DuBow
Michael
M
D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D001426:Bacterial Proteins / Q000378:metabolism*; D001435:Bacteriophages / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D020869:Gene Expression Profiling / Q000379:methods; D016679:Genome, Viral; D006801:Humans; D020543:Proteome / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D013204:Staphylococcus Phages / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000378:metabolism* / Q000821:virology*; D014764:Viral Proteins / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D020543:Proteome; D014764:Viral Proteins