{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:11:57Z","timestamp":1791223917789,"version":"4.1.0"},"reference-count":29,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2013,7,1]],"date-time":"2013-07-01T00:00:00Z","timestamp":1372636800000},"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":[[2013,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    New classes of antiparasitic drugs active against\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trypanosoma brucei<\/jats:named-content>\n                    are needed to combat human African trypanosomiasis. Inhibitors of methionyl-tRNA synthetase (MetRS) have excellent potential to be developed for this purpose (S. Shibata, J. R. Gillespie, A. M. Kelley, A. J. Napuli, Z. Zhang, K. V. Kovzun, R. M. Pefley, J. Lam, F. H. Zucker, W. C. Van Voorhis, E. A. Merritt, W. G. Hol, C. L. Verlinde, E. Fan, and F. S. Buckner, Antimicrob. Agents Chemother.\n                    <jats:bold>55<\/jats:bold>\n                    :1982\u20131989, 2011). In order to assess the potential for resistance to develop against this new class of inhibitors,\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. brucei<\/jats:named-content>\n                    cultures were grown in the presence of MetRS inhibitors or comparison drugs. Resistance up to \u223c50 times the baseline 50% inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) was induced against a MetRS inhibitor after \u223c120 days. A similar level of resistance to the clinical drug eflornithine was induced after \u223c50 days and for pentamidine after \u223c80 days. Thus, resistance was induced more slowly against MetRS inhibitors than against clinically used drugs. The parasites resistant to the MetRS inhibitor were shown to overexpress MetRS mRNA by a factor of 35 over the parental strain. Southern analysis indicated that the MetRS gene was amplified in the genome by nearly 8-fold. When injected into mice, the MetRS inhibitor-resistant parasites caused a reduced level of infection, indicating that the changes associated with resistance attenuated their virulence. This finding and the fact that resistance to MetRS inhibitors developed relatively slowly are encouraging for further development of this class of compounds. Published studies on other antitrypanosomal drugs have primarily shown that alterations in membrane transporters were the mechanisms responsible for resistance. This is the first published report of induced drug resistance in the African trypanosome due to overexpression of the target enzyme.\n                  <\/jats:p>","DOI":"10.1128\/aac.02578-12","type":"journal-article","created":{"date-parts":[[2013,4,15]],"date-time":"2013-04-15T21:48:44Z","timestamp":1366062524000},"page":"3021-3028","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["Induced Resistance to Methionyl-tRNA Synthetase Inhibitors in Trypanosoma brucei Is Due to Overexpression of the Target"],"prefix":"10.1128","volume":"57","author":[{"given":"Ranae M.","family":"Ranade","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Robert","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe L. M. J.","family":"Verlinde","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erkang","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wim G. 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