An Artificial Pathway to 3,4-Dihydroxybenzoic Acid Allows Generation of New Aminocoumarin Antibiotic Recognized by Catechol Transporters of E. coli Silke.

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Presentation transcript:

An Artificial Pathway to 3,4-Dihydroxybenzoic Acid Allows Generation of New Aminocoumarin Antibiotic Recognized by Catechol Transporters of E. coli Silke Alt, Nadja Burkard, Andreas Kulik, Stephanie Grond, Lutz Heide Chemistry & Biology Volume 18, Issue 3, Pages 304-313 (March 2011) DOI: 10.1016/j.chembiol.2010.12.016 Copyright © 2011 Elsevier Ltd Terms and Conditions

Chemistry & Biology 2011 18, 304-313DOI: (10. 1016/j. chembiol. 2010 Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 1 The Aminocoumarin Antibiotics Novobiocin and Clorobiocin Chemistry & Biology 2011 18, 304-313DOI: (10.1016/j.chembiol.2010.12.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 2 Substrate Tolerance of Different Aminocoumarin Acyl Ligases Activity of different aminocoumarin acyl ligases with acyl substrates containing catechol motifs. Amide bond formation was determined with 3-amino-4,7-dihydroxy-8-methyl-coumarin as amino substrate in the presence of ATP and Mg2+, as described in the Experimental Procedures. Chemistry & Biology 2011 18, 304-313DOI: (10.1016/j.chembiol.2010.12.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 3 Strategy for the Generation of a Clorobiocin Derivative Containing a 3,4-Dihydroxybenzoyl Moiety The sequence of the synthetic ubiC/pobA operon is shown in Figure S1. Chemistry & Biology 2011 18, 304-313DOI: (10.1016/j.chembiol.2010.12.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 4 HPLC and LC-MS Analysis (A) HPLC chromatogram of a culture extract from the heterologous producer strain Streptomyces coelicolor M512(clo-SA2)/pSA11 cultivated in CDM medium. (B) Purified compound isolated from cultures in CDM medium. (C) Mass spectrometric fragmentation of novclobiocin 401 obtained by selected ion monitoring chromatograms. LC-ESI-MS mass scans were performed in negative mode for m/z 643. The suggested fragmentation scheme for the compound is shown. Chemistry & Biology 2011 18, 304-313DOI: (10.1016/j.chembiol.2010.12.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 5 Determination of the Inhibitory Activity by Supercoiling and Decatenation Assays Supercoiling (A) and decatenation (B) assays with E. coli and S. aureus DNA gyrase and topoisomerase IV. The first lane labeled with C contains control assays without enzyme. The lane labeled 0 contains assays with addition of 3 μl solvent (5% aqueous DMSO). The following lanes contain assays to which the indicated amount of antibiotic, dissolved in 5% DMSO, has been added. In the supercoiling assays, the lower band shows supercoiled pBR322 DNA, formed under catalysis of DNA gyrase. In the decatenation assays, the lower band shows decatenated kinetoplast DNA, formed under catalysis of topoisomerase IV. Chemistry & Biology 2011 18, 304-313DOI: (10.1016/j.chembiol.2010.12.016) Copyright © 2011 Elsevier Ltd Terms and Conditions

Figure 6 Determination of the Antibacterial Activity by Disk Diffusion Assays The antibacterial activity of clorobiocin, novobiocin, and novclobiocin 401 was determined against E. coli mutants with and without active TonB. To improve visualization of the inhibition zones, living cells were stained with 2,3,5-triphenyltetrazolium chloride. Chemistry & Biology 2011 18, 304-313DOI: (10.1016/j.chembiol.2010.12.016) Copyright © 2011 Elsevier Ltd Terms and Conditions