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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2007-6-21
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
1747-0277
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pubmed:author |
pubmed-author:BalliDarlene JDJ,
pubmed-author:BaranowskiJohn LJL,
pubmed-author:BetzSteven FSF,
pubmed-author:BeutelBruce ABA,
pubmed-author:Black-SchaeferCandace LCL,
pubmed-author:CaiMengliM,
pubmed-author:ChovanLinda ELE,
pubmed-author:ClarkRichard FRF,
pubmed-author:CoenMichael LML,
pubmed-author:ComessKenneth MKM,
pubmed-author:CooperCurt SCS,
pubmed-author:DorwinSarah ASA,
pubmed-author:EdaljiRohintonR,
pubmed-author:FeiR WRW,
pubmed-author:FesikStephen WSW,
pubmed-author:FlorjancicAlan SAS,
pubmed-author:GuYu-GuiYG,
pubmed-author:HajdukPhilip JPJ,
pubmed-author:HarlanJohn EJE,
pubmed-author:HebertEric JEJ,
pubmed-author:HolzmanThomas FTF,
pubmed-author:KakavasStephan JSJ,
pubmed-author:LernerClaude GCG,
pubmed-author:MackJamey CJC,
pubmed-author:McCallJ OwenJO,
pubmed-author:MertaPhilip JPJ,
pubmed-author:MetzgerRandy ERE,
pubmed-author:NiliusAngela MAM,
pubmed-author:SaikiAnne YAY,
pubmed-author:SandersWilliam JWJ,
pubmed-author:SchurdakMark EME,
pubmed-author:SearleXenia BXB,
pubmed-author:ShivakumarAnnapur GAG,
pubmed-author:SmithRichard ARA,
pubmed-author:SoniNiruN,
pubmed-author:ThornewellSusan JSJ,
pubmed-author:WagenaarFrank LFL,
pubmed-author:WagnerRolfR,
pubmed-author:WalterKarl AKA,
pubmed-author:WoodallCharlotteC,
pubmed-author:YuLipingL,
pubmed-author:ZhangTianyuanT
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pubmed:issnType |
Print
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pubmed:volume |
69
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
395-404
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pubmed:meshHeading |
pubmed-meshheading:17581233-Adenosine Triphosphatases,
pubmed-meshheading:17581233-Amino Acid Sequence,
pubmed-meshheading:17581233-Animals,
pubmed-meshheading:17581233-Anti-Bacterial Agents,
pubmed-meshheading:17581233-B-Lymphocytes,
pubmed-meshheading:17581233-Bacterial Proteins,
pubmed-meshheading:17581233-Chemistry, Pharmaceutical,
pubmed-meshheading:17581233-Drug Design,
pubmed-meshheading:17581233-Genome, Bacterial,
pubmed-meshheading:17581233-Genomics,
pubmed-meshheading:17581233-Haemophilus influenzae,
pubmed-meshheading:17581233-Magnetic Resonance Spectroscopy,
pubmed-meshheading:17581233-Mass Spectrometry,
pubmed-meshheading:17581233-Molecular Sequence Data,
pubmed-meshheading:17581233-Protein Binding,
pubmed-meshheading:17581233-Structure-Activity Relationship
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pubmed:year |
2007
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pubmed:articleTitle |
From bacterial genomes to novel antibacterial agents: discovery, characterization, and antibacterial activity of compounds that bind to HI0065 (YjeE) from Haemophilus influenzae.
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pubmed:affiliation |
Abbott Global Pharmaceutical Research and Development, Abbott Park, IL 60064-6098, USA.
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pubmed:publicationType |
Journal Article
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