{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T07:06:08Z","timestamp":1792220768229,"version":"4.4.0"},"reference-count":36,"publisher":"Microbiology Society","issue":"12","license":[{"start":{"date-parts":[[2021,12,24]],"date-time":"2021-12-24T00:00:00Z","timestamp":1640304000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"crossref","award":["BB\/R012504\/1"],"award-info":[{"award-number":["BB\/R012504\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"crossref","award":["BBS\/E\/F\/000PR10349"],"award-info":[{"award-number":["BBS\/E\/F\/000PR10349"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,24]]},"abstract":"<jats:p>Trimethoprim and sulfamethoxazole are used commonly together as cotrimoxazole for the treatment of urinary tract and other infections. The evolution of resistance to these and other antibacterials threatens therapeutic options for clinicians. We generated and analysed a chemical-biology-whole-genome data set to predict new targets for antibacterial combinations with trimethoprim and sulfamethoxazole. For this we used a large transposon mutant library in <jats:italic>\n                     <jats:named-content content-type=\"species\">\n                        <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/doi.org\/10.1601\/nm.3093\" xlink:type=\"simple\">Escherichia coli<\/jats:ext-link>\n                     <\/jats:named-content>\n                  <\/jats:italic> BW25113 where an outward-transcribing inducible promoter was engineered into one end of the transposon. This approach allows regulated expression of adjacent genes in addition to gene inactivation at transposon insertion sites, a methodology that has been called TraDIS-<jats:italic>Xpress<\/jats:italic>. These chemical genomic data sets identified mechanisms for both reduced and increased susceptibility to trimethoprim and sulfamethoxazole. The data identified that over-expression of FolA reduced trimethoprim susceptibility, a known mechanism for reduced susceptibility. In addition, transposon insertions into the genes <jats:italic>tdk<\/jats:italic>, <jats:italic>deoR<\/jats:italic>, <jats:italic>ybbC<\/jats:italic>, <jats:italic>hha<\/jats:italic>, <jats:italic>ldcA<\/jats:italic>, <jats:italic>wbbK<\/jats:italic> and <jats:italic>waaS<\/jats:italic> increased susceptibility to trimethoprim and likewise for <jats:italic>rsmH<\/jats:italic>, <jats:italic>fadR<\/jats:italic>, <jats:italic>ddlB<\/jats:italic>, <jats:italic>nlpI<\/jats:italic> and <jats:italic>prc<\/jats:italic> with sulfamethoxazole, while insertions in <jats:italic>ispD<\/jats:italic>, <jats:italic>uspC<\/jats:italic>, <jats:italic>minC<\/jats:italic>, <jats:italic>minD<\/jats:italic>, <jats:italic>yebK<\/jats:italic>, <jats:italic>truD<\/jats:italic> and <jats:italic>umpG<\/jats:italic> increased susceptibility to both these antibiotics. Two of these genes\u2019 products, Tdk and IspD, are inhibited by AZT and fosmidomycin respectively, antibiotics that are known to synergise with trimethoprim. Thus, the data identified two known targets and several new target candidates for the development of co-drugs that synergise with trimethoprim, sulfamethoxazole or cotrimoxazole. We demonstrate that the TraDIS-<jats:italic>Xpress<\/jats:italic> technology can be used to generate information-rich chemical-genomic data sets that can be used for antibacterial development.<\/jats:p>","DOI":"10.1099\/mgen.0.000718","type":"journal-article","created":{"date-parts":[[2021,12,7]],"date-time":"2021-12-07T17:15:31Z","timestamp":1638897331000},"source":"Crossref","is-referenced-by-count":12,"title":["Chemical biology-whole genome engineering datasets predict new antibacterial combinations"],"prefix":"10.1099","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3680-6343","authenticated-orcid":false,"given":"Arthur K.","family":"Turner","sequence":"first","affiliation":[{"name":"Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9437-2996","authenticated-orcid":false,"given":"Muhammad","family":"Yasir","sequence":"additional","affiliation":[{"name":"Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9002-1822","authenticated-orcid":false,"given":"Sarah","family":"Bastkowski","sequence":"additional","affiliation":[{"name":"Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-281X","authenticated-orcid":false,"given":"Andrea","family":"Telatin","sequence":"additional","affiliation":[{"name":"Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6919-6062","authenticated-orcid":false,"given":"Andrew","family":"Page","sequence":"additional","affiliation":[{"name":"University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK"},{"name":"Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9169-7592","authenticated-orcid":false,"given":"Mark","family":"Webber","sequence":"additional","affiliation":[{"name":"University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK"},{"name":"Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2423-1167","authenticated-orcid":false,"given":"Ian","family":"Charles","sequence":"additional","affiliation":[{"name":"University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK"},{"name":"Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"345","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkx504"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1038\/s41429-019-0240-6"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5296"},{"key":"R4","article-title":"Global prevalence of antibiotic resistance in paediatric urinary tract infections caused by Escherichia coli and association with routine use of antibiotics in primary care: systematic review and meta-analysis","volume":"352","author":"Bryce","year":"2016","journal-title":"BMJ"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2015.02.022"},{"key":"R6","doi-asserted-by":"crossref","first-page":"e103","DOI":"10.1093\/cid\/ciq257","article-title":"International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases","volume":"52","author":"Gupta","year":"2011","journal-title":"Clin Infect Dis"},{"key":"R7","doi-asserted-by":"crossref","first-page":"7656752","DOI":"10.1155\/2018\/7656752","article-title":"Community-acquired urinary tract infection by Escherichia coli in the era of antibiotic resistance","volume":"2018","author":"Lee","year":"2018","journal-title":"Biomed Res Int"},{"key":"R8","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1093\/jac\/47.5.599","article-title":"The prevalence of trimethoprim-resistance-conferring dihydrofolate reductase genes in urinary isolates of Escherichia coli in Korea","volume":"47","author":"Lee","year":"2001","journal-title":"J Antimicrob Chemother"},{"key":"R9","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1128\/AAC.06060-11","article-title":"In vitro antimicrobial resistance of urinary Escherichia coli isolates among U.S. outpatients from 2000 to 2010","volume":"56","author":"Sanchez","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"key":"R10","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.015008-0"},{"key":"R11","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky373"},{"key":"R12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jgar.2019.06.016"},{"key":"R13","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1517\/14656566.2.8.1227","article-title":"Fluoroquinolones in the treatment of acute uncomplicated urinary tract infections in adult women","volume":"2","author":"Garrison","year":"2001","journal-title":"Expert Opin Pharmacother"},{"key":"R14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1987.tb10664.x"},{"key":"R15","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02381-18"},{"key":"R16","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2009.02.001"},{"key":"R17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2007.05801.x"},{"key":"R18","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1111\/j.1574-6968.2000.tb08906.x","article-title":"Characterisation of two new gene cassettes, aadA5 and dfrA17","volume":"182","author":"White","year":"2000","journal-title":"FEMS Microbiol Lett"},{"key":"R19","doi-asserted-by":"publisher","DOI":"10.1101\/gr.254391.119"},{"key":"R20","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100050"},{"key":"R21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1007980"},{"key":"R22","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btw022"},{"key":"R23","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr703"},{"key":"R24","volume-title":"Gephi: an open source software for exploring and manipulating networks, in International AAAI Conference on Weblogs and Social Media","author":"Bastian","year":"2009"},{"key":"R25","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"R26","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1093\/jac\/dkaa204","article-title":"A whole-genome screen identifies Salmonella enterica serovar Typhi genes involved in fluoroquinolone susceptibility","volume":"75","author":"Turner","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"R27","doi-asserted-by":"crossref","first-page":"3144","DOI":"10.1093\/jac\/dkaa296","article-title":"A genome-wide analysis of Escherichia coli responses to fosfomycin using TraDIS-Xpress reveals novel roles for phosphonate degradation and phosphate transport systems","volume":"75","author":"Turner","year":"2020","journal-title":"J Antimicrob Chemother"},{"key":"R28","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.31.2.274"},{"key":"R29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2001644"},{"key":"R30","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-018-0041-4"},{"key":"R31","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.11.052"},{"key":"R32","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1128\/AAC.22.4.560","article-title":"Synergy of fosmidomycin (FR-31564) and other antimicrobial agents","volume":"22","author":"Neu","year":"1982","journal-title":"Antimicrob Agents Chemother"},{"key":"R33","doi-asserted-by":"crossref","first-page":"3570","DOI":"10.1021\/bi200113y","article-title":"A second target of the antimalarial and antibacterial agent fosmidomycin revealed by cellular metabolic profiling","volume":"50","author":"Zhang","year":"2011","journal-title":"Biochemistry"},{"key":"R34","doi-asserted-by":"publisher","DOI":"10.1099\/mgen.0.000086"},{"key":"R35","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw1003"},{"key":"R36","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky964"}],"container-title":["Microbial Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/mgen\/10.1099\/mgen.0.000718?crawler=true&mimetype=application\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T22:22:40Z","timestamp":1702592560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.microbiologyresearch.org\/content\/journal\/mgen\/10.1099\/mgen.0.000718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,24]]},"references-count":36,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12,24]]}},"URL":"https:\/\/doi.org\/10.1099\/mgen.0.000718","relation":{},"ISSN":["2057-5858"],"issn-type":[{"value":"2057-5858","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,24]]}}}