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Antimicrobial Agents and Chemotherapy, May 2007, p. 1760-1769, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01267-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Defining the Molecular Forces That Determine the Impact of Neomycin on Bacterial Protein Synthesis: Importance of the 2'-Amino Functionality{triangledown} ,{dagger}

Christopher M. Barbieri,1 Malvika Kaul,1 Melanie Bozza-Hingos,1 Fang Zhao,2 Yitzhak Tor,2 Thomas Hermann,2 and Daniel S. Pilch1*

Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, New Jersey 08854-5635,1 Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-03582

Received 10 October 2006/ Returned for modification 4 January 2007/ Accepted 4 March 2007

2-Deoxystreptamine (2-DOS) aminoglycosides exert their antibiotic actions by binding to the A site of the 16S rRNA and interfering with bacterial protein synthesis. However, the molecular forces that govern the antitranslational activities of aminoglycosides are poorly understood. Here, we describe studies aimed at elucidating these molecular forces. In this connection, we compare the bactericidal, antitranslational, and rRNA binding properties of the 4,5-disubstituted 2-DOS aminoglycoside neomycin (Neo) and a conformationally restricted analog of Neo (CR-Neo) in which the 2'-nitrogen atom is covalently conjugated to the 5''-carbon atom. The bactericidal potency of Neo exceeds that of CR-Neo, with this enhanced antibacterial activity reflecting a correspondingly enhanced antitranslational potency. Time-resolved fluorescence anisotropy studies suggest that the enhanced antitranslational potency of Neo relative to that of CR-Neo is due to a greater extent of drug-induced reduction in the mobilities of the nucleotides at positions 1492 and 1493 of the rRNA A site. Buffer- and salt-dependent binding studies, coupled with high-resolution structural information, point to electrostatic contacts between the 2'-amino functionality of Neo and the host rRNA as being an important modulator of 1492 and 1493 base mobilities and therefore antitranslational activities.

* Corresponding author. Mailing address: UMDNJ-Robert Wood Johnson Medical School, Department of Pharmacology, 675 Hoes Lane, Piscataway, NJ 08854-5635. Phone: (732) 235-3352. Fax: (732) 235-4073. E-mail: pilchds{at}umdnj.edu

{triangledown} Published ahead of print on 12 March 2007.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, May 2007, p. 1760-1769, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01267-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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