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Antimicrobial Agents and Chemotherapy, August 2008, p. 2806-2812, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00247-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Discovery and Characterization of QPT-1, the Progenitor of a New Class of Bacterial Topoisomerase Inhibitors{triangledown} ,{dagger}

Alita A. Miller,*{ddagger} Gordon L. Bundy,§ John E. Mott, Jill E. Skepner,{ddagger} Timothy P. Boyle, Douglas W. Harris,|| Alexander E. Hromockyj, Keith R. Marotti,|| Gary E. Zurenko,{dagger}{dagger} Jennifer B. Munzner,{ddagger} Michael T. Sweeney,|| Gary F. Bammert,|| Judith C. Hamel,{ddagger} Charles W. Ford,|| Wei-Zhu Zhong,{ddagger}{ddagger} David R. Graber,§ Gary E. Martin,§§ Fusen Han,¶¶ Lester A. Dolak,§ Eric P. Seest,|||| J. Craig Ruble,|||| Gregg M. Kamilar,{dagger}{dagger}{dagger} John R. Palmer,|||| Lee S. Banitt,|||| Alexander R. Hurd,{ddagger}{ddagger}{ddagger} and Michael R. Barbachyn§§§

Infectious Diseases Biology and Medicinal Chemistry, Pharmacia Corporation, 301 Henrietta St., Kalamazoo, Michigan 49001

Received 22 February 2008/ Returned for modification 6 May 2008/ Accepted 26 May 2008

QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (–)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibiotic-resistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the β subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.

* Corresponding author. Present address: Antibacterial Discovery Biology, Pfizer Global Research & Development, Eastern Point Rd., Groton, CT 06340. Phone: (860) 686-6808. Fax: (860) 715-4693. E-mail: alita.a.miller{at}pfizer.com

{triangledown} Published ahead of print on 2 June 2008.

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

{ddagger} Present address: Pfizer Global Research & Development, Eastern Point Rd., Groton, CT 06340.

§ Retired.

Present address: Pfizer Global Research & Development, 700 Chesterfield Parkway West, Chesterfield, MO 63017.

|| Present address: Pfizer Animal Health, 301 Henrietta St., Kalamazoo, MI 49007.

{dagger}{dagger} Present address: Micromyx, 4717 Campus Dr., Kalamazoo, MI 49008.

{ddagger}{ddagger} Present address: Pfizer Global Research & Development, 10724 Science Center Drive, San Diego, CA 92121.

§§ Present address: Schering-Plough, 556 Morris Ave., Summit, NJ 07901.

¶¶ Present address: Tiens Biotech Group, 6 Yuanquan Road, Wuqing New-tech Industrial Park, Tianjin, China.

|||| Present address: Lilly Research Labs, Eli Lilly & Company, Indianapolis, IN 46285.

{dagger}{dagger}{dagger} Present address: Pfizer Global Research & Development, Cambridge, MA 02139.

{ddagger}{ddagger}{ddagger} Present address: Lycera Corporation, 930 N. University, Ann Arbor, MI 48109.

§§§ Present address: AstraZeneca Pharmaceuticals LP, 35 Gatehouse Drive, Waltham, MA 02451.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2806-2812, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00247-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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