{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T20:19:43Z","timestamp":1776025183476,"version":"3.50.1"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"12","license":[{"start":{"date-parts":[[2011,12,1]],"date-time":"2011-12-01T00:00:00Z","timestamp":1322697600000},"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":[[2011,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            PA-824 is a promising drug candidate for the treatment of tuberculosis (TB). It is in phase II clinical trials as part of the first newly designed regimen containing multiple novel antituberculosis drugs (PA-824 in combination with moxifloxacin and pyrazinamide). However, given that the genes involved in resistance against PA-824 are not fully conserved in the\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium tuberculosis<\/jats:named-content>\n            complex (MTBC), this regimen might not be equally effective against different MTBC genotypes. To investigate this question, we sequenced two PA-824 resistance genes (\n            <jats:italic>fgd1<\/jats:italic>\n            [\n            <jats:italic>Rv0407<\/jats:italic>\n            ] and\n            <jats:italic>ddn<\/jats:italic>\n            [\n            <jats:italic>Rv3547<\/jats:italic>\n            ]) in 65 MTBC strains representing major phylogenetic lineages. The MICs of representative strains were determined using the modified proportion method in the Bactec MGIT 960 system. Our analysis revealed single-nucleotide polymorphisms in both genes that were specific either for several genotypes or for individual strains, yet none of these mutations significantly affected the PA-824 MICs (\u22640.25 \u03bcg\/ml). These results were supported by\n            <jats:italic>in silico<\/jats:italic>\n            modeling of the mutations identified in Fgd1. In contrast, \u201c\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Mycobacterium canettii<\/jats:named-content>\n            \u201d strains displayed a higher MIC of 8 \u03bcg\/ml. In conclusion, we found a large genetic diversity in PA-824 resistance genes that did not lead to elevated PA-824 MICs. In contrast,\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. canettii<\/jats:named-content>\n            strains had MICs that were above the plasma concentrations of PA-824 documented so far in clinical trials. As\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. canettii<\/jats:named-content>\n            is also intrinsically resistant against pyrazinamide, new regimens containing PA-824 and pyrazinamide might not be effective in treating\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">M. canettii<\/jats:named-content>\n            infections. This finding has implications for the design of multiple ongoing clinical trials.\n          <\/jats:p>","DOI":"10.1128\/aac.05500-11","type":"journal-article","created":{"date-parts":[[2011,9,20]],"date-time":"2011-09-20T08:18:33Z","timestamp":1316506713000},"page":"5718-5722","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":61,"title":["Impact of\n            <i>fgd1<\/i>\n            and\n            <i>ddn<\/i>\n            Diversity in Mycobacterium tuberculosis Complex on\n            <i>In Vitro<\/i>\n            Susceptibility to PA-824"],"prefix":"10.1128","volume":"55","author":[{"given":"Silke","family":"Feuerriegel","sequence":"first","affiliation":[{"name":"Molecular Mycobacteriology, Research Center Borstel, Borstel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio U.","family":"K\u00f6ser","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Ba\u00f9","sequence":"additional","affiliation":[{"name":"Structural Genomics Laboratory, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"R\u00fcsch-Gerdes","sequence":"additional","affiliation":[{"name":"National Reference Center for Mycobacteria, Research Center Borstel, Borstel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David K.","family":"Summers","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of Cambridge, Cambridge, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John A. C.","family":"Archer","sequence":"additional","affiliation":[{"name":"Computational Bioscience Research Center, King Abdullah University of Science and Technology, Thuwal, Kingdom of Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc A.","family":"Marti-Renom","sequence":"additional","affiliation":[{"name":"Structural Genomics Laboratory, Centro de Investigaci\u00f3n Pr\u00edncipe Felipe, Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Niemann","sequence":"additional","affiliation":[{"name":"Molecular Mycobacteriology, Research Center Borstel, Borstel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00849-10"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl092"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2010.04.008"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801854200"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.184.9.2420-2428.2002"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.183.24.7058-7066.2001"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007815"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01354-09"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00536-10"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.meegid.2010.07.016"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030449"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.2165\/11538170-000000000-00000"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00106-09"},{"key":"e_1_3_3_15_2","unstructured":"Global Alliance for TB Drug Development. 2011. 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