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Antimicrobial Agents and Chemotherapy, December 2005, p. 4942-4949, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4942-4949.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Structure-Guided Discovery of Novel Aminoglycoside Mimetics as Antibacterial Translation Inhibitors

Yuefen Zhou,¹ Vlad E. Gregor,^1, Zhongxiang Sun,¹ Benjamin K. Ayida,¹ Geoffrey C. Winters,^1, Douglas Murphy,¹ Klaus B. Simonsen,^1, Dionisios Vourloumis,^1,¶ Sarah Fish,¹ Jamie M. Froelich,¹ Daniel Wall,^1* and Thomas Hermann^2*

Anadys Pharmaceuticals, San Diego, California,¹ Department of Chemistry and Biochemistry, University of California—San Diego, La Jolla, California²

Received 17 August 2005/ Returned for modification 30 September 2005/ Accepted 4 October 2005

We report the structure-guided discovery, synthesis, and initial characterization of 3,5-diamino-piperidinyl triazines (DAPT), a novel translation inhibitor class that targets bacterial rRNA and exhibits broad-spectrum antibacterial activity. DAPT compounds were designed as structural mimetics of aminoglycoside antibiotics which bind to the bacterial ribosomal decoding site and thereby interfere with translational fidelity. We found that DAPT compounds bind to oligonucleotide models of decoding-site RNA, inhibit translation in vitro, and induce translation misincorporation in vivo, in agreement with a mechanism of action at the ribosomal decoding site. The novel DAPT antibacterials inhibit growth of gram-positive and gram-negative bacteria, including the respiratory pathogen Pseudomonas aeruginosa, and display low toxicity to human cell lines. In a mouse protection model, an advanced DAPT compound demonstrated efficacy against an Escherichia coli infection at a 50% protective dose of 2.4 mg/kg of body weight by single-dose intravenous administration.

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* Corresponding author. Mailing address: Department of Chemistry and Biochemistry, University of California—San Diego, 9500 Gilman Drive 0358, La Jolla, CA 92093-0358. Phone for Thomas Hermann: (858) 534-4467. Fax: (858) 534-0202. E-mail: tch{at}ucsd.edu. Phone for Daniel Wall: (858) 530-3711. Fax: (858) 530-3644. E-mail: dwall{at}anadyspharma.com.

Present address: ChemBridge Research Laboratories, San Diego, Calif.

Present address: QLT, Inc., Vancouver, British Columbia, Canada.

Present address: H. Lundbeck A/S, Valby, Copenhagen, Denmark.

^¶ Present address: National Centre for Scientific Research "Democritos," Athens, Greece.

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Antimicrobial Agents and Chemotherapy, December 2005, p. 4942-4949, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.4942-4949.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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