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Antimicrobial Agents and Chemotherapy, August 2006, p. 2707-2712, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00012-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Novel Bacterial Acetyl Coenzyme A Carboxylase Inhibitors with Antibiotic Efficacy In Vivo

C. Freiberg,^* J. Pohlmann, P. G. Nell, R. Endermann, J. Schuhmacher, B. Newton, M. Otteneder, T. Lampe, D. Häbich, and K. Ziegelbauer

Pharma Research & Development, Discovery Europe, Bayer Health Care AG, D-42096 Wuppertal, Germany

Received 5 January 2006/ Returned for modification 6 March 2006/ Accepted 11 May 2006

The pseudopeptide pyrrolidinedione antibiotics, such as moiramide B, have recently been discovered to target the multisubunit acetyl coenzyme A (acetyl-CoA) carboxylases of bacteria. In this paper, we describe synthetic variations of each moiety of the modularly composed pyrrolidinediones, providing insight into structure-activity relationships of biochemical target activity, in vitro potency, and in vivo efficacy. The novel derivatives showed highly improved activities against gram-positive bacteria compared to those of previously reported variants. The compounds exhibited a MIC₉₀ value of 0.1 µg/ml against a broad spectrum of Staphylococcus aureus clinical isolates. No cross-resistance to antibiotics currently used in clinical practice was observed. Resistance mutations induced by pyrrolidinediones are exclusively located in the carboxyltransferase subunits of the bacterial acetyl-CoA carboxylase, indicating the identical mechanisms of action of all derivatives tested. Improvement of the physicochemical profile was achieved by salt formation, leading to aqueous solubilities of up to 5 g/liter. For the first time, the in vitro activity of this compound class was compared with its in vivo efficacy, demonstrating a path from compounds weakly active in vivo to agents with significant efficacy. In a murine model of S. aureus sepsis, the 100% effective dose of the best compound reported was 25 mg/kg of body weight, only fourfold higher than that of the comparator molecule linezolid. The obvious improvements achieved by chemical derivatization reflect the potential of this novel antibiotic compound class for future therapy.

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* Corresponding author. Present address: Department of Chemistry, Niederrhein University of Applied Sciences, Adlerstrasse 32, D-47798 Krefeld, Germany. Phone: 49-2151-822-4060. Fax: 49-2151-822-4073. E-mail: christoph.freiberg{at}hs-niederrhein.de.

Present address: Basilea Pharmaceutica AG, Grenzacherstrasse 487, CH-4005 Basel, Switzerland.

Present address: GE Healthcare, Amersham Place, Little Chalfont, Buckinghamshire HP7 9NA, United Kingdom.

Present address: F. Hoffmann-La Roche, Drug Metabolism and Pharmacokinetics, Non-Clinical Drug Safety, CH-4070 Basel, Switzerland.

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Antimicrobial Agents and Chemotherapy, August 2006, p. 2707-2712, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00012-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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