{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:35:08Z","timestamp":1790984108238,"version":"4.1.0"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"11","license":[{"start":{"date-parts":[[2013,11,1]],"date-time":"2013-11-01T00:00:00Z","timestamp":1383264000000},"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":[[2013,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The activity of aminoglycosides, which are used to treat\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Pseudomonas aeruginosa<\/jats:named-content>\n            respiratory infection in cystic fibrosis (CF) patients, is reduced under the anaerobic conditions that reflect the CF lung\n            <jats:italic>in vivo<\/jats:italic>\n            . In contrast, a 4:1 (wt\/wt) combination of fosfomycin and tobramycin (F:T), which is under investigation for use in the treatment of CF lung infection, has increased activity against\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n            under anaerobic conditions. The aim of this study was to elucidate the mechanisms underlying the increased activity of F:T under anaerobic conditions. Microarray analysis was used to identify the transcriptional basis of increased F:T activity under anaerobic conditions, and key findings were confirmed by microbiological tests, including nitrate utilization assays, growth curves, and susceptibility testing. Notably, growth in subinhibitory concentrations of F:T, but not tobramycin or fosfomycin alone, significantly downregulated (\n            <jats:italic>P<\/jats:italic>\n            &lt; 0.05) nitrate reductase genes\n            <jats:italic>narG<\/jats:italic>\n            and\n            <jats:italic>narH<\/jats:italic>\n            , which are essential for normal anaerobic growth of\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n            . Under anaerobic conditions, F:T significantly decreased (\n            <jats:italic>P<\/jats:italic>\n            &lt; 0.001) nitrate utilization in\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n            strains PAO1, PA14, and PA14\n            <jats:italic>lasR<\/jats:italic>\n            ::Gm, a mutant known to exhibit increased nitrate utilization. A similar effect was observed with two clinical\n            <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n            isolates. Growth curves indicate that nitrate reductase transposon mutants had reduced growth under anaerobic conditions, with these mutants also having increased susceptibility to F:T compared to the wild type under similar conditions. The results of this study suggest that downregulation of nitrate reductase genes resulting in reduced nitrate utilization is the mechanism underlying the increased activity of F:T under anaerobic conditions.\n          <\/jats:p>","DOI":"10.1128\/aac.00750-13","type":"journal-article","created":{"date-parts":[[2013,8,20]],"date-time":"2013-08-20T01:58:37Z","timestamp":1376963917000},"page":"5406-5414","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":23,"title":["Fosfomycin and Tobramycin in Combination Downregulate Nitrate Reductase Genes\n            <i>narG<\/i>\n            and\n            <i>narH<\/i>\n            , Resulting in Increased Activity against Pseudomonas aeruginosa under Anaerobic Conditions"],"prefix":"10.1128","volume":"57","author":[{"given":"Gerard","family":"McCaughey","sequence":"first","affiliation":[{"name":"CF and Airways Microbiology Research Group, Queen's University, Belfast, United Kingdom"},{"name":"School of Pharmacy, Queen's University, Belfast, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre F.","family":"Gilpin","sequence":"additional","affiliation":[{"name":"CF and Airways Microbiology Research Group, Queen's University, Belfast, United Kingdom"},{"name":"School of Pharmacy, Queen's University, Belfast, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thamarai","family":"Schneiders","sequence":"additional","affiliation":[{"name":"Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas R.","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"McKevitt","sequence":"additional","affiliation":[{"name":"Gilead Sciences, Inc., Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Stuart","family":"Elborn","sequence":"additional","affiliation":[{"name":"CF and Airways Microbiology Research Group, Queen's University, Belfast, United Kingdom"},{"name":"Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael M.","family":"Tunney","sequence":"additional","affiliation":[{"name":"CF and Airways Microbiology Research Group, Queen's University, Belfast, United Kingdom"},{"name":"School of Pharmacy, Queen's University, Belfast, United 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