From bacterial genomes to novel antibacterial agents: discovery, characterization, and antibacterial activity of compounds that bind to HI0065 (YjeE) from Haemophilus influenzae.
As part of a fully integrated and comprehensive strategy to discover novel antibacterial agents, NMR- and mass spectrometry-based affinity selection screens were performed to identify compounds that bind to protein targets uniquely found in bacteria and encoded by genes essential for microbial viability. A biphenyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein HI0065, a member of a family of probable ATP-binding proteins found exclusively in eubacteria. The structure-activity relationships developed around the NMR-derived biphenyl acid lead were consistent with on-target antibacterial activity as the Staphylococcus aureus antibacterial activity of the series correlated extremely well with binding affinity to HI0065, while the correlation of binding affinity with B-cell cytotoxicity was relatively poor. Although further studies are needed to conclusively establish the mode of action of the biphenyl series, these compounds represent novel leads that can serve as the basis for the development of novel antibacterial agents that appear to work via an unprecedented mechanism of action. Overall, these results support the genomics-driven hypothesis that targeting bacterial essential gene products that are not present in eukaryotic cells can identify novel antibacterial agents.
Lerner
Claude G
CG
Abbott Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6098, USA.
Hajduk
Philip J
PJ
Wagner
Rolf
R
Wagenaar
Frank L
FL
Woodall
Charlotte
C
Gu
Yu-Gui
YG
Searle
Xenia B
XB
Florjancic
Alan S
AS
Zhang
Tianyuan
T
Clark
Richard F
RF
Cooper
Curt S
CS
Mack
Jamey C
JC
Yu
Liping
L
Cai
Mengli
M
Betz
Steven F
SF
Chovan
Linda E
LE
McCall
J Owen
JO
Black-Schaefer
Candace L
CL
Kakavas
Stephan J
SJ
Schurdak
Mark E
ME
Comess
Kenneth M
KM
Walter
Karl A
KA
Edalji
Rohinton
R
Dorwin
Sarah A
SA
Smith
Richard A
RA
Hebert
Eric J
EJ
Harlan
John E
JE
Metzger
Randy E
RE
Merta
Philip J
PJ
Baranowski
John L
JL
Coen
Michael L
ML
Thornewell
Susan J
SJ
Shivakumar
Annapur G
AG
Saiki
Anne Y
AY
Soni
Niru
N
Bui
Mai
M
Balli
Darlene J
DJ
Sanders
William J
WJ
Nilius
Angela M
AM
Holzman
Thomas F
TF
Fesik
Stephen W
SW
Beutel
Bruce A
BA
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001402:B-Lymphocytes / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D016680:Genome, Bacterial; D023281:Genomics; D006193:Haemophilus influenzae / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011485:Protein Binding; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D000251:Adenosine Triphosphatases; C465440:YjeE protein, Haemophilus influenzae