Novel antibacterial class.
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.
Dandliker
Peter J
PJ
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. peter.dandliker@abbott.com
Pratt
Steve D
SD
Nilius
Angela M
AM
Black-Schaefer
Candace
C
Ruan
Xiaoan
X
Towne
Danli L
DL
Clark
Richard F
RF
Englund
Erika E
EE
Wagner
Rolf
R
Weitzberg
Moshe
M
Chovan
Linda E
LE
Hickman
Robert K
RK
Daly
Melissa M
MM
Kakavas
Stephan
S
Zhong
Ping
P
Cao
Zhensheng
Z
David
Caroline A
CA
Xuei
Xiaoling
X
Lerner
Claude G
CG
Soni
Niru B
NB
Bui
Mai
M
Shen
Linus L
LL
Cai
Yingna
Y
Merta
Philip J
PJ
Saiki
Anne Y C
AY
Beutel
Bruce A
BA
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
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