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Antimicrobial Agents and Chemotherapy, June 2008, p. 1982-1990, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01235-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Biological Activities of Novel Gyrase Inhibitors of the Aminocoumarin Class{triangledown}

Christine Anderle,1 Martin Stieger,2 Matthew Burrell,3 Stefan Reinelt,2 Anthony Maxwell,3 Malcolm Page,2 and Lutz Heide1*

Pharmazeutische Biologie, Pharmazeutisches Institut, Universität Tübingen, Auf der Morgenstelle 8, Tübingen D-72076, Germany,1 Basilea Pharmaceutica AG, Grenzacherstr. 487, Basel CH-4005, Switzerland,2 Department of Biological Chemistry, John Innes Centre, Colney, Norwich NR4 7UH, United Kingdom3

Received 20 September 2007/ Returned for modification 11 February 2008/ Accepted 6 March 2008

Thirty-one aminocoumarin antibiotics derived from mutasynthesis experiments were investigated for their biological activities. Their inhibitory activities toward Escherichia coli DNA gyrase were determined in two different in vitro assays: an ATPase assay and a DNA supercoiling assay. The assays gave a similar rank order of the activities of the compounds tested, although the absolute 50% inhibitory concentrations (IC50s) obtained in each assay were different. To confirm that the compounds also acted as gyrase inhibitors in vivo, reporter gene assays were carried out with E. coli by using gyrA and sulA promoter fusions with the luxCDABE operon. A strong induction of both promoters was observed for those compounds that showed gyrase inhibitory activity in the biochemical assays. Compounds carrying analogs of the prenylated benzoyl moiety (ring A) of clorobiocin that were structurally very different showed high levels of activity both in the biochemical assay and in the reporter gene assay, indicating that the structure of this moiety can be varied considerably without a loss of affinity for bacterial gyrase. The experimentally determined IC50s were compared to the binding energies calculated in silico, which indicated that a shift of the pyrrole carboxylic acid moiety from the O-3'' to the O-2'' position of the deoxysugar moiety has a significant impact on the binding mode of the compounds. The aminocoumarin compounds were also investigated for their MICs against different bacterial pathogens. Several compounds showed high levels of activity against staphylococci, including a methicillin-resistant Staphylococcus aureus strain. However, they showed only poor activities against gram-negative strains.

* Corresponding author. Mailing address: Pharmazeutische Biologie, Pharmazeutisches Institut, Universität Tübingen, Auf der Morgenstelle 8, Tübingen D-72076, Germany. Phone: 49-7071-29-72460. Fax: 49-7071-29-5250. E-mail: heide{at}uni-tuebingen.de

{triangledown} Published ahead of print on 17 March 2008.

Antimicrobial Agents and Chemotherapy, June 2008, p. 1982-1990, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01235-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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