title: From bacterial genomes to novel antibacterial agents: discovery, characterization, and antibacterial activity of compounds that bind to HI0065 (YjeE) from Haemophilus influenzae.
abstract: 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.
authors.affiliation: Abbott Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6098, USA.
authors.forename: Claude G
authors.initials: CG
authors.lastname: Lerner
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.forename: Frank L
authors.initials: FL
authors.lastname: Wagenaar
authors.forename: Charlotte
authors.initials: C
authors.lastname: Woodall
authors.forename: Yu-Gui
authors.initials: YG
authors.lastname: Gu
authors.forename: Xenia B
authors.initials: XB
authors.lastname: Searle
authors.forename: Alan S
authors.initials: AS
authors.lastname: Florjancic
authors.forename: Tianyuan
authors.initials: T
authors.lastname: Zhang
authors.forename: Richard F
authors.initials: RF
authors.lastname: Clark
authors.forename: Curt S
authors.initials: CS
authors.lastname: Cooper
authors.forename: Jamey C
authors.initials: JC
authors.lastname: Mack
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Mengli
authors.initials: M
authors.lastname: Cai
authors.forename: Steven F
authors.initials: SF
authors.lastname: Betz
authors.forename: Linda E
authors.initials: LE
authors.lastname: Chovan
authors.forename: J Owen
authors.initials: JO
authors.lastname: McCall
authors.forename: Candace L
authors.initials: CL
authors.lastname: Black-Schaefer
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Kakavas
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schurdak
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Comess
authors.forename: Karl A
authors.initials: KA
authors.lastname: Walter
authors.forename: Rohinton
authors.initials: R
authors.lastname: Edalji
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Dorwin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Smith
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Hebert
authors.forename: John E
authors.initials: JE
authors.lastname: Harlan
authors.forename: Randy E
authors.initials: RE
authors.lastname: Metzger
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.forename: John L
authors.initials: JL
authors.lastname: Baranowski
authors.forename: Michael L
authors.initials: ML
authors.lastname: Coen
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Thornewell
authors.forename: Annapur G
authors.initials: AG
authors.lastname: Shivakumar
authors.forename: Anne Y
authors.initials: AY
authors.lastname: Saiki
authors.forename: Niru
authors.initials: N
authors.lastname: Soni
authors.forename: Mai
authors.initials: M
authors.lastname: Bui
authors.forename: Darlene J
authors.initials: DJ
authors.lastname: Balli
authors.forename: William J
authors.initials: WJ
authors.lastname: Sanders
authors.forename: Angela M
authors.initials: AM
authors.lastname: Nilius
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Holzman
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Beutel
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D000251:Adenosine Triphosphatases; C465440:YjeE protein, Haemophilus influenzae