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Journal of Bacteriology, October 2009, p. 6273-6280, Vol. 191, No. 20
0021-9193/09/$08.00+0     doi:10.1128/JB.00829-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Synthetic Microcin C Analogs Targeting Different Aminoacyl-tRNA Synthetases{triangledown}

Pieter Van de Vijver,2,{dagger} Gaston H. M. Vondenhoff,1,2,{dagger} Teymur S. Kazakov,1,{dagger} Ekaterina Semenova,1 Konstantin Kuznedelov,1 Anastasia Metlitskaya,3 Arthur Van Aerschot,2 and Konstantin Severinov2,3,4*

Waksman Institute, Rutgers University, the State University of New Jersey, Piscataway, New Jersey 08854,2 Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia,4 Rega Institute for Medical Research, Medicinal Chemistry, Minderbroedersstraat 10, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium,1 Institutes of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia3

Received 25 June 2009/ Accepted 4 August 2009

Microcin C (McC) is a potent antibacterial agent produced by some strains of Escherichia coli. McC consists of a ribosomally synthesized heptapeptide with a modified AMP attached through a phosphoramidate linkage to the {alpha}-carboxyl group of the terminal aspartate. McC is a Trojan horse inhibitor: it is actively taken inside sensitive cells and processed there, and the product of processing, a nonhydrolyzable aspartyl-adenylate, inhibits translation by preventing aminoacylation of tRNAAsp by aspartyl-tRNA synthetase (AspRS). Changing the last residue of the McC peptide should result in antibacterial compounds with targets other than AspRS. However, mutations that introduce amino acid substitutions in the last position of the McC peptide abolish McC production. Here, we report total chemical synthesis of three McC-like compounds containing a terminal aspartate, glutamate, or leucine attached to adenosine through a nonhydrolyzable sulfamoyl bond. We show that all three compounds function in a manner similar to that of McC, but the first compound inhibits bacterial growth by targeting AspRS while the latter two inhibit, respectively, GluRS and LeuRS. Our approach opens a way for creation of new antibacterial Trojan horse agents that target any 1 of the 20 tRNA synthetases in the cell.

* Corresponding author. Mailing address: Waksman Institute, 190 Frelinghuysen Road, Piscataway, NJ 08854. Phone: (732) 445-6095. Fax: (732) 445-5735. E-mail: severik{at}waksman.rutgers.edu

{triangledown} Published ahead of print on 14 August 2009.

{dagger} P. Van de Vijver, G. H. M. Vondenhoff, and T. S. Kazakov contributed equally to this work.

Journal of Bacteriology, October 2009, p. 6273-6280, Vol. 191, No. 20
0021-9193/09/$08.00+0     doi:10.1128/JB.00829-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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