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Antimicrobial Agents and Chemotherapy, June 2006, p. 2178-2184, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00140-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Molecular Validation of LpxC as an Antibacterial Drug Target in Pseudomonas aeruginosa

Khisimuzi E. Mdluli,1,{dagger} Pamela R. Witte,1,{ddagger} Toni Kline,2,§ Adam W. Barb,3 Alice L. Erwin,1* Bryce E. Mansfield,1,¶ Amanda L. McClerren,3,|| Michael C. Pirrung,4,§§ L. Nathan Tumey,3,# Paul Warrener,1,{dagger}{dagger} Christian R. H. Raetz,3 and C. Kendall Stover1,{ddagger}{ddagger}

Departments of Research Biology,1 Chemistry, Chiron Corporation, 201 Elliott Avenue West, Suite 150, Seattle, Washington 98119,2 Departments of Biochemistry,3 Chemistry, Duke University Medical Center, Durham, North Carolina 277104

Received 2 February 2006/ Returned for modification 2 March 2006/ Accepted 24 March 2006

LpxC [UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc deacetylase] is a metalloamidase that catalyzes the first committed step in the biosynthesis of the lipid A component of lipopolysaccharide. A previous study (H. R. Onishi, B. A. Pelak, L. S. Gerckens, L. L. Silver, F. M. Kahan, M. H. Chen, A. A. Patchett, S. M. Galloway, S. A. Hyland, M. S. Anderson, and C. R. H. Raetz, Science 274:980-982, 1996) identified a series of synthetic LpxC-inhibitory molecules that were bactericidal for Escherichia coli. These molecules did not inhibit the growth of Pseudomonas aeruginosa and were therefore not developed further as antibacterial drugs. The inactivity of the LpxC inhibitors for P. aeruginosa raised the possibility that LpxC activity might not be essential for all gram-negative bacteria. By placing the lpxC gene of P. aeruginosa under tight control of an arabinose-inducible promoter, we demonstrated the essentiality of LpxC activity for P. aeruginosa. It was found that compound L-161,240, the most potent inhibitor from the previous study, was active against a P. aeruginosa construct in which the endogenous lpxC gene was inactivated and in which LpxC activity was supplied by the lpxC gene from E. coli. Conversely, an E. coli construct in which growth was dependent on the P. aeruginosa lpxC gene was resistant to the compound. The differential activities of L-161,240 against the two bacterial species are thus the result primarily of greater potency toward the E. coli enzyme rather than of differences in the intrinsic resistance of the bacteria toward antibacterial compounds due to permeability or efflux. These data validate P. aeruginosa LpxC as a target for novel antibiotic drugs and should help direct the design of inhibitors against clinically important gram-negative bacteria.

* Corresponding author. Present address: Microbial Pathogens Program, Seattle Biomedical Research Institute, 307 Westlake Ave. N., Seattle, WA 98109. Phone: (206) 256-7431. Fax: (206) 256-7229. E-mail: alice.erwin{at}sbri.org.

{dagger} Present address: Global Alliance for TB Drug Discovery, New York, NY 10004.

{ddagger} Present address: deCODE Biostructures, Bainbridge Island, WA 98110.

§ Present address: Department of Genome Sciences, University of Washington, Seattle, WA 98195.

Present address: Department of Pathobiology, University of Washington, Seattle, WA 98195.

|| Present address: Department of Chemistry, University of Illinois, Urbana-Champaign, IL 61801.

§§ Present address: Department of Chemistry, University of California at Riverside, Riverside, CA 92521.

# Present address: Wyeth Research, Pearl River, NY 10965.

{dagger}{dagger} Present address: Rosetta Inpharmatics LLC, Seattle, WA 98109.

{ddagger}{ddagger} Present address: Pfizer Corporation, Ann Arbor, MI 48105.

Antimicrobial Agents and Chemotherapy, June 2006, p. 2178-2184, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00140-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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