{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:11:18Z","timestamp":1791277878712,"version":"4.1.0"},"reference-count":28,"publisher":"American Chemical Society (ACS)","issue":"12","license":[{"start":{"date-parts":[[2015,10,13]],"date-time":"2015-10-13T00:00:00Z","timestamp":1444694400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA077373"],"award-info":[{"award-number":["R01CA077373"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI073491"],"award-info":[{"award-number":["R01AI073491"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI87671"],"award-info":[{"award-number":["R01AI87671"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Widespread fluoroquinolone resistance has drawn attention to quinazolinediones (diones), fluoroquinolone-like topoisomerase poisons that are unaffected by common quinolone-resistance mutations. To better understand differences between quinolones and diones, we examined their impact on the formation of cleaved complexes (drug\u2013topoisomerase\u2013DNA complexes in which the DNA moiety is broken) with gyrase, one of two bacterial targets of the drugs. Formation of cleaved complexes, measured by linearization of a circular DNA substrate, required lower concentrations of quinolone than dione. The reverse reaction, detected as resealing of DNA breaks in cleaved complexes, required higher temperatures and EDTA concentrations for quinolones than diones. The greater stability of quinolone-containing complexes was attributed to the unique ability of the quinolone C3\/C4 keto acid to complex with magnesium and form a previously described drug\u2013magnesium\u2013water bridge with GyrA-Ser83 and GyrA-Asp87. A nearby substitution in GyrA (G81C) reduced activity differences between quinolone and dione, indicating that resistance due to this variation derives from perturbation of the magnesium\u2013water bridge. To increase dione activity, we examined a relatively small, flexible C-7-3-(aminomethyl)pyrrolidinyl substituent, which is distal to the bridging C3\/C4 keto acid substituent of quinolones. The 3-(aminomethyl)pyrrolidinyl group at position C-7 was capable of forming binding interactions with GyrB-Glu466, as indicated by inspection of crystal structures, computer-aided docking, and measurement of cleaved-complex formation with mutant and wild-type GyrB proteins. Thus, modification of dione C-7 substituents constitutes a strategy for obtaining compounds active against common quinolone-resistant mutants.<\/jats:p>","DOI":"10.1021\/cb500629k","type":"journal-article","created":{"date-parts":[[2014,10,13]],"date-time":"2014-10-13T13:07:33Z","timestamp":1413205653000},"page":"2895-2904","source":"Crossref","is-referenced-by-count":39,"title":["Bypassing Fluoroquinolone Resistance with Quinazolinediones:\nStudies of Drug\u2013Gyrase\u2013DNA Complexes Having Implications\nfor Drug Design"],"prefix":"10.1021","volume":"9","author":[{"given":"Karl","family":"Drlica","sequence":"first","affiliation":[{"name":"New Jersey Medical School, Rutgers Biomedical and Health Sciences , , 225 Warren Street , , ,","place":["Newark, New Jersey, United States, 07103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkady","family":"Mustaev","sequence":"additional","affiliation":[{"name":"New Jersey Medical School, Rutgers Biomedical and Health Sciences , , 225 Warren Street , , ,","place":["Newark, New Jersey, United States, 07103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyrell R.","family":"Towle","sequence":"additional","affiliation":[{"name":"University of Iowa College of Pharmacy , , 115 South Grand Avenue , , ,","place":["Iowa City, Iowa, United States, 52246"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gan","family":"Luan","sequence":"additional","affiliation":[{"name":"New Jersey Medical School, Rutgers Biomedical and Health Sciences , , 225 Warren Street , , ,","place":["Newark, New Jersey, United States, 07103"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Kerns","sequence":"additional","affiliation":[{"name":"University of Iowa College of Pharmacy , , 115 South Grand Avenue , , ,","place":["Iowa City, Iowa, United States, 52246"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Berger","sequence":"additional","affiliation":[{"name":"University of California , , Stanley Hall, , ,","place":["Berkeley, California, United States, 94720"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,10,13]]},"reference":[{"key":"2026090117452628000_cit1","doi-asserted-by":"crossref","first-page":"4303","DOI":"10.1021\/bi00388a018","article-title":"Calcium-promoted DNA cleavage by eukaryotic topoisomerase\nII: trapping the covalent enzyme-DNA complex in an active form","volume":"26","author":"Osheroff","year":"1987","journal-title":"Biochemistry"},{"key":"2026090117452628000_cit2","doi-asserted-by":"crossref","first-page":"12031","DOI":"10.1073\/pnas.91.25.12031","article-title":"Disruption of a\ntopoisomerase\u2013DNA cleavage complex by a DNA helicase","volume":"91","author":"Howard","year":"1994","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090117452628000_cit3","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0022-2836(79)90077-9","article-title":"DNA gyrase on the bacterial chromosome: DNA cleavage\ninduced by oxolinic acid","volume":"131","author":"Snyder","year":"1979","journal-title":"J. Mol. Biol."},{"key":"2026090117452628000_cit4","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1128\/AAC.01617-06","article-title":"Quinolone-mediated\nbacterial death","volume":"52","author":"Drlica","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090117452628000_cit5","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1128\/jb.140.2.424-435.1979","article-title":"Escherichia coli mutants thermosensitive\nfor deoxyribonucleic acid gyrase subunit A: effects on deoxyribonucleic\nacid replication, transcription, and bacteriophage growth","volume":"140","author":"Kreuzer","year":"1979","journal-title":"J. Bacteriol."},{"key":"2026090117452628000_cit6","doi-asserted-by":"crossref","first-page":"12300","DOI":"10.1074\/jbc.M113.529164","article-title":"Fluoroquinolone\u2013gyrase\u2013DNA\ncomplexes: two modes of drug binding","volume":"289","author":"Mustaev","year":"2014","journal-title":"J. Biol.\nChem."},{"key":"2026090117452628000_cit7","doi-asserted-by":"crossref","first-page":"4772","DOI":"10.1073\/pnas.74.11.4772","article-title":"Nalidixic\nacid resistance: a second genetic character involved in DNA gyrase\nactivity","volume":"74","author":"Gellert","year":"1977","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2026090117452628000_cit8","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1073\/pnas.74.11.4767","article-title":"Mechanism\nof action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and\na novel nicking-closing enzyme","volume":"74","author":"Sugino","year":"1977","journal-title":"Proc. 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Struct. Mol. Biol."},{"key":"2026090117452628000_cit13","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nature09197","article-title":"Type IIA topoisomerase\ninhibition by a new class of antibacterial agents","volume":"466","author":"Bax","year":"2010","journal-title":"Nature"},{"key":"2026090117452628000_cit14","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/nsmb.1892","article-title":"Structural\nbasis of quinolone inhibition of type IIA topoisomerases and target-mediated\nresistance","volume":"17","author":"Wohlkonig","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026090117452628000_cit15","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1039\/c003759a","article-title":"The use of divalent\nmetal ions by type II topoisomerases","volume":"2","author":"Deweese","year":"2010","journal-title":"Metallomics"},{"key":"2026090117452628000_cit16","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1021\/bi2013905","article-title":"Drug interactions with Bacillus anthracis topoisomerase IV: biochemical basis for quinolone\naction and resistance","volume":"51","author":"Aldred","year":"2012","journal-title":"Biochemistry"},{"key":"2026090117452628000_cit17","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1128\/AAC.00113-09","article-title":"Probing\nthe differential interactions\nof quinazolinedione PD 0305970 and quinolones with gyrase and topoisomerase\nIV","volume":"53","author":"Pan","year":"2009","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090117452628000_cit18","doi-asserted-by":"crossref","first-page":"2660","DOI":"10.1021\/cb400592n","article-title":"Overcoming\ntarget-mediated\nquinolone resistance in topoisomerase IV by introducing metal ion-independent\ndrug-enzyme interactions: implications for drug design","volume":"8","author":"Aldred","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"2026090117452628000_cit19","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1128\/AAC.00330-08","article-title":"Use of gyrase\nresistance mutants to guide selection of 8-methoxy-quinazoline-2,4-diones","volume":"52","author":"German","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090117452628000_cit20","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1128\/AAC.00033-11","article-title":"Fluoroquinolone and quinazolinedione\nactivities against wild-type and gyrase mutant strains of Mycobacterium smegmatis","volume":"55","author":"Malik","year":"2011","journal-title":"Antimicrob.\nAgents Chemother."},{"key":"2026090117452628000_cit21","doi-asserted-by":"crossref","first-page":"3011","DOI":"10.1128\/AAC.00190-10","article-title":"Comparison of in vitro activities of fluoroquinolone-like 2,4- and 1.3-diones","volume":"54","author":"Oppegard","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090117452628000_cit22","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/S0022-2836(02)00049-9","article-title":"The role of GyrB in the DNA cleavage\u2013religation\nreaction of DNA gyrase: a proposed two metal-ion mechanism","volume":"318","author":"Noble","year":"2002","journal-title":"J. Mol. Biol."},{"key":"2026090117452628000_cit23","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1093\/nar\/gkr018","article-title":"Use of divalent metal ions in the\nDNA cleavage reaction of topoisomerase IV","volume":"39","author":"Pitts","year":"2011","journal-title":"Nucleic\nAcids Res."},{"key":"2026090117452628000_cit24","doi-asserted-by":"crossref","first-page":"8421","DOI":"10.1016\/S0021-9258(20)82081-X","article-title":"Double strand DNA cleavage\nby type II DNA topoisomerase from Drosophila melanogaster","volume":"258","author":"Sander","year":"1983","journal-title":"J. Biol.\nChem."},{"key":"2026090117452628000_cit25","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1093\/jac\/dkr566","article-title":"A systematic review\nof gyrase mutations associated with fluoroquinolone-resistant Mycobacterium tuberculosis and a proposed gyrase numbering\nsystem","volume":"67","author":"Maruri","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"2026090117452628000_cit26","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1126\/science.1204117","article-title":"Structural basis of type II topoisomerase\ninhibition by the anticancer drug etoposide","volume":"333","author":"Wu","year":"2011","journal-title":"Science"},{"key":"2026090117452628000_cit27","doi-asserted-by":"crossref","first-page":"7830","DOI":"10.1093\/nar\/gkq665","article-title":"A domain insertion in Escherichia coli GyrB adopts a novel fold that plays a critical role in gyrase function","volume":"38","author":"Schoeffler","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2026090117452628000_cit28","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1021\/jm020406h","article-title":"Surflex: fully\nautomatic flexible molecular docking using a molecular similarity-based\nsearch engine","volume":"46","author":"Jain","year":"2003","journal-title":"J. Med. Chem."}],"container-title":["ACS Chemical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/cb500629k","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/9\/12\/2895\/15723328\/cb500629k.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/9\/12\/2895\/15723328\/cb500629k.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:45:34Z","timestamp":1788299134000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acbcct\/article\/9\/12\/2895\/1479023\/Bypassing-Fluoroquinolone-Resistance-with"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,10,13]]},"references-count":28,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2014,10,13]]},"published-print":{"date-parts":[[2014,12,19]]}},"URL":"https:\/\/doi.org\/10.1021\/cb500629k","relation":{},"ISSN":["1554-8929","1554-8937"],"issn-type":[{"value":"1554-8929","type":"print"},{"value":"1554-8937","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,13]]}}}