{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:48:53Z","timestamp":1791308933221,"version":"4.3.1"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2004,2,1]],"date-time":"2004-02-01T00:00:00Z","timestamp":1075593600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2004,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Phenylalanyl (Phe)-tRNA synthetase (Phe-RS) is an essential enzyme which catalyzes the transfer of phenylalanine to the Phe-specific transfer RNA (tRNA\n                    <jats:sup>Phe<\/jats:sup>\n                    ), 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\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    ,\n                    <jats:italic>Haemophilus influenzae<\/jats:italic>\n                    ,\n                    <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n                    , and\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    , 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\n                    <jats:italic>Staphylococcus<\/jats:italic>\n                    ,\n                    <jats:italic>Streptococcus<\/jats:italic>\n                    ,\n                    <jats:italic>Haemophilus<\/jats:italic>\n                    , and\n                    <jats:italic>Moraxella<\/jats:italic>\n                    strains, reaching MICs below 1 \u03bcg\/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 tRNA\n                    <jats:sup>Phe<\/jats:sup>\n                    charging is the antibacterial principle of this compound class was obtained by proteome analysis of\n                    <jats:italic>Bacillus subtilis<\/jats:italic>\n                    . Here, the phenyl-thiazolylurea-sulfonamides induced a protein pattern indicative of the stringent response. In addition, an\n                    <jats:italic>E. coli<\/jats:italic>\n                    strain carrying a\n                    <jats:italic>relA<\/jats:italic>\n                    mutation and defective in stringent response was more susceptible than its isogenic\n                    <jats:italic>relA<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    parent strain. In vivo efficacy was investigated in a murine\n                    <jats:italic>S. aureus<\/jats:italic>\n                    sepsis model and a\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1128\/aac.48.2.525-532.2004","type":"journal-article","created":{"date-parts":[[2004,1,24]],"date-time":"2004-01-24T18:46:39Z","timestamp":1074969999000},"page":"525-532","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":67,"title":["New Class of Bacterial Phenylalanyl-tRNA Synthetase Inhibitors with High Potency and Broad-Spectrum Activity"],"prefix":"10.1128","volume":"48","author":[{"given":"Dieter","family":"Beyer","sequence":"first","affiliation":[{"name":"Department of Anti-Infectives"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hein-Peter","family":"Kroll","sequence":"additional","affiliation":[{"name":"Department of Anti-Infectives"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Endermann","sequence":"additional","affiliation":[{"name":"Department of Anti-Infectives"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"Schiffer","sequence":"additional","affiliation":[{"name":"Department of Anti-Infectives"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Siegel","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Pharma Research, Bayer Healthcare AG, D-42096 Wuppertal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Bauser","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Pharma Research, Bayer Healthcare AG, D-42096 Wuppertal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens","family":"Pohlmann","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Pharma Research, Bayer Healthcare AG, D-42096 Wuppertal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Brands","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Pharma Research, Bayer Healthcare AG, D-42096 Wuppertal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Ziegelbauer","sequence":"additional","affiliation":[{"name":"Department of Anti-Infectives"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter","family":"Haebich","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Pharma Research, Bayer Healthcare AG, D-42096 Wuppertal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Eymann","sequence":"additional","affiliation":[{"name":"Institute for Microbiology, Ernst-Moritz-Arndt-University, 17489 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Bro\u0308tz-Oesterhelt","sequence":"additional","affiliation":[{"name":"Department of Anti-Infectives"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1021\/jm00233a002","volume":"19","year":"1976","unstructured":"Anderson, R. 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