This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shen, L. L.
Right arrow Articles by Beutel, B. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shen, L. L.
Right arrow Articles by Beutel, B. A.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2005, p. 1890-1897, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1890-1897.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mechanism of Action of a Novel Series of Naphthyridine-Type Ribosome Inhibitors: Enhancement of tRNA Footprinting at the Decoding Site of 16S rRNA

Linus L. Shen,* Candace Black-Schaefer, Yingna Cai, Peter J. Dandliker, and Bruce A. Beutel

Infectious Diseases Research, Abbott Laboratories, Abbott Park, Illinois 60064

Received 21 July 2004/ Returned for modification 1 October 2004/ Accepted 4 January 2005

The novel ribosome inhibitors (NRIs) are a broad-spectrum naphthyridine class that selectively inhibits bacterial protein synthesis (P. J. Dandliker et al., Antimicrob. Agents Chemother. 47:3831-3839, 2003). Footprinting experiments, using a range of NRIs and chemical modification agents on Escherichia coli ribosomes, revealed no evidence for direct protection of rRNA. In the presence of tRNA, however, we found that NRIs enhanced the known ribosomal footprinting pattern of tRNA in a dose-dependent manner. The most prominent increase in protection, at A1492/3 and A1413 in helix-44 of 16S RNA, strictly required the presence of tRNA and poly(U), and the effect was correlated with the potency of the inhibitor. Radioligand binding studies with inhibitor [3H]A-424902 showed that the compound binds to tRNA, either in its charged or uncharged form. The dissociation constant for [3H]A-424902 binding to Phe-tRNAPhe was determined to be 1.8 µM, near its translation inhibition potency of 1.6 µM in a cell-free S. pneumoniae extract assay. The compound did not change the binding of radiolabeled tRNA to the 30S ribosomal subunit. Taken together, these results imply that the NRIs exert their effects on protein synthesis by structurally perturbing the tRNA/30S complex at the decoding site.

* Corresponding author. Mailing address: Abbott Laboratories, Department R47R, Bldg. AP10, 100 Abbott Park Rd., Abbott Park, IL 60064-6099. Phone: (847) 937-5983. Fax: (847) 938-1674. E-mail: linus.l.shen{at}abbott.com.

Antimicrobial Agents and Chemotherapy, May 2005, p. 1890-1897, Vol. 49, No. 5
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.5.1890-1897.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Buurman, E. T., Johnson, K. D., Kelly, R. K., MacCormack, K. (2006). Different Modes of Action of Naphthyridones in Gram-Positive and Gram-Negative Bacteria. Antimicrob. Agents Chemother. 50: 385-387 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»