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Antimicrobial Agents and Chemotherapy, February 2004, p. 525-532, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.525-532.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

New Class of Bacterial Phenylalanyl-tRNA Synthetase Inhibitors with High Potency and Broad-Spectrum Activity

Dieter Beyer,1 Hein-Peter Kroll,1 Rainer Endermann,1 Guido Schiffer,1 Stephan Siegel,2 Marcus Bauser,2 Jens Pohlmann,2 Michael Brands,2 Karl Ziegelbauer,1 Dieter Haebich,2 Christine Eymann,3 and Heike Brötz-Oesterhelt1*

Department of Anti-Infectives,1 Department of Chemistry, Pharma Research, Bayer Healthcare AG, D-42096 Wuppertal,2 Institute for Microbiology, Ernst-Moritz-Arndt-University, 17489 Greifswald, Germany3

Received 27 May 2003/ Returned for modification 24 August 2003/ Accepted 14 October 2003

Phenylalanyl (Phe)-tRNA synthetase (Phe-RS) is an essential enzyme which catalyzes the transfer of phenylalanine to the Phe-specific transfer RNA (tRNAPhe), a key step in protein biosynthesis. Phenyl-thiazolylurea-sulfonamides were identified as a novel class of potent inhibitors of bacterial Phe-RS by high-throughput screening and chemical variation of the screening hit. The compounds inhibit Phe-RS of Escherichia coli, Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus, with 50% inhibitory concentrations in the nanomolar range. Enzyme kinetic measurements demonstrated that the compounds bind competitively with respect to the natural substrate Phe. All derivatives are highly selective for the bacterial Phe-RS versus the corresponding mammalian cytoplasmic and human mitochondrial enzymes. Phenyl-thiazolylurea-sulfonamides displayed good in vitro activity against Staphylococcus, Streptococcus, Haemophilus, and Moraxella strains, reaching MICs below 1 µg/ml. The antibacterial activity was partly antagonized by increasing concentrations of Phe in the culture broth in accordance with the competitive binding mode. Further evidence that inhibition of tRNAPhe charging is the antibacterial principle of this compound class was obtained by proteome analysis of Bacillus subtilis. Here, the phenyl-thiazolylurea-sulfonamides induced a protein pattern indicative of the stringent response. In addition, an E. coli strain carrying a relA mutation and defective in stringent response was more susceptible than its isogenic relA+ parent strain. In vivo efficacy was investigated in a murine S. aureus sepsis model and a S. pneumoniae sepsis model in rats. Treatment with the phenyl-thiazolylurea-sulfonamides reduced the bacterial titer in various organs by up to 3 log units, supporting the potential value of Phe-RS as a target in antibacterial therapy.

* Corresponding author. Mailing address: Bayer Healthcare AG, Antibacterial Research, Pharma Research Center, Aprather Weg 18a, D-42096 Wuppertal, Germany. Phone: (49) 202 364561. Fax: (49) 202 364116. E-mail: heike.broetz-oesterhelt.hb{at}bayer-ag.de.

Antimicrobial Agents and Chemotherapy, February 2004, p. 525-532, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.525-532.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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