{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T16:11:45Z","timestamp":1791130305743,"version":"4.1.0"},"reference-count":35,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2005,8,1]],"date-time":"2005-08-01T00:00:00Z","timestamp":1122854400000},"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":[[2005,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            <jats:italic>Haemophilus influenzae<\/jats:italic>\n            isolates vary widely in their susceptibilities to the peptide deformylase inhibitor LBM415 (MIC range, 0.06 to 32 \u03bcg\/ml); however, on average, they are less susceptible than gram-positive organisms, such as\n            <jats:italic>Staphylococcus aureus<\/jats:italic>\n            and\n            <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n            . Insertional inactivation of the\n            <jats:italic>H. influenzae acrB<\/jats:italic>\n            or\n            <jats:italic>tolC<\/jats:italic>\n            gene in strain NB65044 (Rd strain KW20) increased susceptibility to LBM415, confirming a role for the AcrAB-TolC pump in determining resistance. Consistent with this, sequencing of a PCR fragment generated with primers flanking the\n            <jats:italic>acrRA<\/jats:italic>\n            region from an LBM415-hypersusceptible\n            <jats:italic>H. influenzae<\/jats:italic>\n            clinical isolate revealed a genetic deletion of\n            <jats:italic>acrA<\/jats:italic>\n            . Inactivation of\n            <jats:italic>acrB<\/jats:italic>\n            or\n            <jats:italic>tolC<\/jats:italic>\n            in several clinical isolates with atypically reduced susceptibility to LBM415 (MIC of 16 \u03bcg\/ml or greater) significantly increased susceptibility, confirming that the pump is also a determinant of decreased susceptibility in these clinical isolates. Examination of\n            <jats:italic>acrR<\/jats:italic>\n            , encoding the putative repressor of pump gene expression, from several of these strains revealed mutations introducing frameshifts, stop codons, and amino acid changes relative to the published sequence, suggesting that loss of pump repression leads to decreased susceptibility. Supporting this, NB65044\n            <jats:italic>acrR<\/jats:italic>\n            mutants selected by exposure to LBM415 at 8 \u03bcg\/ml had susceptibilities to LBM415 and other pump substrates comparable to the least sensitive clinical isolates and showed increased expression of pump genes.\n          <\/jats:p>","DOI":"10.1128\/aac.49.8.3129-3135.2005","type":"journal-article","created":{"date-parts":[[2005,7,27]],"date-time":"2005-07-27T10:52:45Z","timestamp":1122461565000},"page":"3129-3135","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":44,"title":["Role of the AcrAB-TolC Efflux Pump in Determining Susceptibility of\n            <i>Haemophilus influenzae<\/i>\n            to the Novel Peptide Deformylase Inhibitor LBM415"],"prefix":"10.1128","volume":"49","author":[{"given":"Charles R.","family":"Dean","sequence":"first","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubha","family":"Narayan","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis M.","family":"Daigle","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JoAnn L.","family":"Dzink-Fox","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Puyang","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn R.","family":"Bracken","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl E.","family":"Dean","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"Weidmann","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyu","family":"Yuan","sequence":"additional","affiliation":[{"name":"Vicuron Pharmaceuticals, Fremont, California 94555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Jain","sequence":"additional","affiliation":[{"name":"Vicuron Pharmaceuticals, Fremont, California 94555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil S.","family":"Ryder","sequence":"additional","affiliation":[{"name":"Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.012602299"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.4.1058-1064.2001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.2001.tb10631.x"},{"key":"e_1_3_2_5_2","unstructured":"Cho D. 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