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J. Biol. Chem., Vol. 279, Issue 25, 26066-26073, June 18, 2004

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Identification and Characterization of the First Class of Potent Bacterial Acetyl-CoA Carboxylase Inhibitors with Antibacterial Activity^*

Christoph Freiberg, Nina A. Brunner, Guido Schiffer, Thomas Lampe¶, Jens Pohlmann¶, Michael Brands¶, Martin Raabe||, Dieter Häbich¶, and Karl Ziegelbauer

From the Institute of Anti-infectives Research, ^¶Institute of Chemistry Research, and ^||Institute of Cardiovascular Research, Pharma Research, Bayer HealthCare AG, D-42096 Wuppertal, Germany

The multisubunit acetyl-CoA carboxylase, which catalyzes the first committed step in fatty acid biosynthesis, is broadly conserved among bacteria. Its rate-limiting role in formation of fatty acids makes this enzyme an attractive target for the design of novel broad-spectrum antibacterials. However, no potent inhibitors have been discovered so far. This report describes the identification and characterization of highly potent bacterial acetyl-CoA carboxylase inhibitors with antibacterial activity for the first time. We demonstrate that pseudopeptide pyrrolidine dione antibiotics such as moiramide B inhibit the Escherichia coli enzyme at nanomolar concentrations. Moiramide B targets the carboxyltransferase reaction of this enzyme with a competitive inhibition pattern versus malonyl-CoA (K_i value = 5 nM). Inhibition at nanomolar concentrations of the pyrrolidine diones is also demonstrated using recombinantly expressed carboxyltransferases from other bacterial species (Staphylococcus aureus, Streptococcus pneumoniae, and Pseudomonas aeruginosa). We isolated pyrrolidine dione-resistant strains of E. coli, S. aureus, and Bacillus subtilis, which contain mutations within the carboxyltransferase subunits AccA or AccD. We demonstrate that such mutations confer resistance to pyrrolidine diones. Inhibition values (IC₅₀) of >100 µM regarding an eukaryotic acetyl-CoA carboxylase from rat liver indicate high selectivity of pyrrolidine diones for the bacterial multisubunit enzyme. The natural product moiramide B and synthetic analogues show broad-spectrum antibacterial activity. The knowledge of the target and the availability of facile assays using carboxyltransferases from different pathogens will enable evaluation of the antibacterial potential of the pyrrolidine diones as a promising antibacterial compound class acting via a novel mode of action.

Received for publication, March 17, 2004

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Bayer HealthCare AG, Pharma Research, Institute of Anti-infectives Research, D-42096 Wuppertal, Germany. Tel.: 49-202-368461; Fax: 49-202-364116; E-mail: christoph.freiberg{at}bayerhealthcare.com.

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