{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:02:12Z","timestamp":1791414132700,"version":"4.3.3"},"reference-count":29,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2015,1,1]],"date-time":"2015-01-01T00:00:00Z","timestamp":1420070400000},"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":[[2015,1]]},"abstract":"ABSTRACT<\/jats:title>\n \n AZD0914 is a new spiropyrimidinetrione bacterial DNA gyrase\/topoisomerase inhibitor with potent\n in vitro<\/jats:italic>\n antibacterial activity against key Gram-positive (\n Staphylococcus aureus<\/jats:named-content>\n ,\n Staphylococcus epidermidis<\/jats:named-content>\n ,\n Streptococcus pneumoniae<\/jats:named-content>\n ,\n Streptococcus pyogenes<\/jats:named-content>\n , and\n Streptococcus agalactiae<\/jats:named-content>\n ), fastidious Gram-negative (\n Haemophilus influenzae<\/jats:named-content>\n and\n Neisseria gonorrhoeae<\/jats:named-content>\n ), atypical (\n Legionella pneumophila<\/jats:named-content>\n ), and anaerobic (\n Clostridium difficile<\/jats:named-content>\n ) bacterial species, including isolates with known resistance to fluoroquinolones. AZD0914 works via inhibition of DNA biosynthesis and accumulation of double-strand cleavages; this mechanism of inhibition differs from those of other marketed antibacterial compounds. AZD0914 stabilizes and arrests the cleaved covalent complex of gyrase with double-strand broken DNA under permissive conditions and thus blocks religation of the double-strand cleaved DNA to form fused circular DNA. Whereas this mechanism is similar to that seen with fluoroquinolones, it is mechanistically distinct. AZD0914 exhibited low frequencies of spontaneous resistance in\n S. aureus<\/jats:named-content>\n , and if mutants were obtained, the mutations mapped to\n gyrB<\/jats:italic>\n . Additionally, no cross-resistance was observed for AZD0914 against recent bacterial clinical isolates demonstrating resistance to fluoroquinolones or other drug classes, including macrolides, \u03b2-lactams, glycopeptides, and oxazolidinones. AZD0914 was bactericidal in both minimum bactericidal concentration and\n in vitro<\/jats:italic>\n time-kill studies. In\n in vitro<\/jats:italic>\n checkerboard\/synergy testing with 17 comparator antibacterials, only additivity\/indifference was observed. The potent\n in vitro<\/jats:italic>\n antibacterial activity (including activity against fluoroquinolone-resistant isolates), low frequency of resistance, lack of cross-resistance, and bactericidal activity of AZD0914 support its continued development.\n <\/jats:p>","DOI":"10.1128\/aac.04124-14","type":"journal-article","created":{"date-parts":[[2014,11,11]],"date-time":"2014-11-11T05:42:42Z","timestamp":1415684562000},"page":"467-474","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":79,"title":["In Vitro<\/i>\n Antibacterial Activity of AZD0914, a New Spiropyrimidinetrione DNA Gyrase\/Topoisomerase Inhibitor with Potent Activity against Gram-Positive, Fastidious Gram-Negative, and Atypical Bacteria"],"prefix":"10.1128","volume":"59","author":[{"given":"Michael D.","family":"Huband","sequence":"first","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia A.","family":"Bradford","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda G.","family":"Otterson","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory S.","family":"Basarab","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy C.","family":"Kutschke","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Giacobbe","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara A.","family":"Patey","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Alm","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele R.","family":"Johnstone","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie E.","family":"Potter","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Miller","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Mueller","sequence":"additional","affiliation":[{"name":"Infection iMed, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1303359"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2010.06.006"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2010.757"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00325-11"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dks162"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1086\/499819"},{"key":"e_1_3_2_8_2","volume-title":"53rd ICAAC","author":"Alm RA","year":"2013","unstructured":"Alm RA, Kutschke A, Otterson LG, Lahiri SD, McLaughlin RE, Lewis LA, Su X, Huband MD, Mueller JP, Gardner H. 2013. 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