title: Novel antibacterial class.
abstract: We report the discovery and characterization of a novel ribosome inhibitor (NRI) class that exhibits selective and broad-spectrum antibacterial activity. Compounds in this class inhibit growth of many gram-positive and gram-negative bacteria, including the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis, and are nontoxic to human cell lines. The first NRI was discovered in a high-throughput screen designed to identify inhibitors of cell-free translation in extracts from S. pneumoniae. The chemical structure of the NRI class is related to antibacterial quinolones, but, interestingly, the differences in structure are sufficient to completely alter the biochemical and intracellular mechanisms of action. Expression array studies and analysis of NRI-resistant mutants confirm this difference in intracellular mechanism and provide evidence that the NRIs inhibit bacterial protein synthesis by inhibiting ribosomes. Furthermore, compounds in the NRI series appear to inhibit bacterial ribosomes by a new mechanism, because NRI-resistant strains are not cross-resistant to other ribosome inhibitors, such as macrolides, chloramphenicol, tetracycline, aminoglycosides, or oxazolidinones. The NRIs are a promising new antibacterial class with activity against all major drug-resistant respiratory pathogens.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. peter.dandliker@abbott.com
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Dandliker
authors.forename: Steve D
authors.initials: SD
authors.lastname: Pratt
authors.forename: Angela M
authors.initials: AM
authors.lastname: Nilius
authors.forename: Candace
authors.initials: C
authors.lastname: Black-Schaefer
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Ruan
authors.forename: Danli L
authors.initials: DL
authors.lastname: Towne
authors.forename: Richard F
authors.initials: RF
authors.lastname: Clark
authors.forename: Erika E
authors.initials: EE
authors.lastname: Englund
authors.forename: Rolf
authors.initials: R
authors.lastname: Wagner
authors.forename: Moshe
authors.initials: M
authors.lastname: Weitzberg
authors.forename: Linda E
authors.initials: LE
authors.lastname: Chovan
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hickman
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Daly
authors.forename: Stephan
authors.initials: S
authors.lastname: Kakavas
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.forename: Zhensheng
authors.initials: Z
authors.lastname: Cao
authors.forename: Caroline A
authors.initials: CA
authors.lastname: David
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xuei
authors.forename: Claude G
authors.initials: CG
authors.lastname: Lerner
authors.forename: Niru B
authors.initials: NB
authors.lastname: Soni
authors.forename: Mai
authors.initials: M
authors.lastname: Bui
authors.forename: Linus L
authors.initials: LL
authors.lastname: Shen
authors.forename: Yingna
authors.initials: Y
authors.lastname: Cai
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Merta
authors.forename: Anne Y C
authors.initials: AY
authors.lastname: Saiki
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Beutel
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics; D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D001419:Bacteria / Q000187:drug effects*; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005057:Eukaryotic Cells / Q000378:metabolism; D017930:Genes, Reporter / Q000235:genetics; D007202:Indicators and Reagents; D008156:Luciferases / Q000235:genetics; D008826:Microbial Sensitivity Tests; D010957:Plasmids / Q000235:genetics; D011817:Rabbits; D012269:Ribosomal Proteins / Q000187:drug effects; D012270:Ribosomes / Q000187:drug effects*; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D000890:Anti-Infective Agents; D007202:Indicators and Reagents; D012269:Ribosomal Proteins; D014157:Transcription Factors; D008156:Luciferases; D001616:beta-Galactosidase; D027081:DNA Gyrase; D000604:Amino Acyl-tRNA Synthetases