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The Phytotoxin Albicidin is a Novel Inhibitor of DNA Gyrase

Saeed M. Hashimi,¹ Melisa K. Wall,^2, Andrew B. Smith,^2, Anthony Maxwell,² and Robert G. Birch^1*

Botany Department—SIB, The University of Queensland, Brisbane 4072, Australia,¹ Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Colney, Norwich NR4 7UH, United Kingdom²

Received 25 July 2006/ Returned for modification 20 September 2006/ Accepted 20 October 2006

Xanthomonas albilineans produces a family of polyketide-peptide compounds called albicidins which are highly potent antibiotics and phytotoxins as a result of their inhibition of prokaryotic DNA replication. Here we show that albicidin is a potent inhibitor of the supercoiling activity of bacterial and plant DNA gyrases, with 50% inhibitory concentrations (40 to 50 nM) less than those of most coumarins and quinolones. Albicidin blocks the religation of the cleaved DNA intermediate during the gyrase catalytic sequence and also inhibits the relaxation of supercoiled DNA by gyrase and topoisomerase IV. Unlike the coumarins, albicidin does not inhibit the ATPase activity of gyrase. In contrast to the quinolones, the albicidin concentration required to stabilize the gyrase cleavage complex increases 100-fold in the absence of ATP. The slow peptide poisons microcin B17 and CcdB also access ATP-dependent conformations of gyrase to block religation, but in contrast to albicidin, they do not inhibit supercoiling under routine assay conditions. Some mutations in gyrA, known to confer high-level resistance to quinolones or CcdB, confer low-level resistance or hypersensitivity to albicidin in Escherichia coli. Within the albicidin biosynthesis region in X. albilineans is a gene encoding a pentapeptide repeat protein designated AlbG that binds to E. coli DNA gyrase and that confers a sixfold increase in the level of resistance to albicidin in vitro and in vivo. These results demonstrate that DNA gyrase is the molecular target of albicidin and that X. albilineans encodes a gyrase-interacting protein for self-protection. The novel features of the gyrase-albicidin interaction indicate the potential for the development of new antibacterial drugs.

Published ahead of print on 30 October 2006.

Present address: Department of Health Sciences & Medicine, Bond University, Queensland, Australia.

Present address: PharmaNet Ltd, Kingsmead Business Park, High Wycombe, HP11 1JU, United Kingdom.

This article has been cited by other articles:

• Hashimi, S. M., Huang, G., Maxwell, A., Birch, R. G. (2008). DNA Gyrase from the Albicidin Producer Xanthomonas albilineans Has Multiple-Antibiotic-Resistance and Unusual Enzymatic Properties. Antimicrob. Agents Chemother. 52: 1382-1390 [Abstract] [Full Text]  
• Renier, A., Vivien, E., Cociancich, S., Letourmy, P., Perrier, X., Rott, P. C., Royer, M. (2007). Substrate Specificity-Conferring Regions of the Nonribosomal Peptide Synthetase Adenylation Domains Involved in Albicidin Pathotoxin Biosynthesis Are Highly Conserved within the Species Xanthomonas albilineans. Appl. Environ. Microbiol. 73: 5523-5530 [Abstract] [Full Text]  
• Vivien, E., Pitorre, D., Cociancich, S., Pieretti, I., Gabriel, D. W., Rott, P. C., Royer, M. (2007). Heterologous Production of Albicidin: a Promising Approach to Overproducing and Characterizing This Potent Inhibitor of DNA Gyrase. Antimicrob. Agents Chemother. 51: 1549-1552 [Abstract] [Full Text]