{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:47:18Z","timestamp":1787168838242,"version":"build-2736575974"},"reference-count":61,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2010,4,1]],"date-time":"2010-04-01T00:00:00Z","timestamp":1270080000000},"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":[[2010,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    OXA \u03b2-lactamases are largely responsible for \u03b2-lactam resistance in\n                    <jats:italic>Acinetobacter<\/jats:italic>\n                    spp. and\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    , two of the most difficult-to-treat nosocomial pathogens. In general, the \u03b2-lactamase inhibitors used in clinical practice (clavulanic acid, sulbactam, and tazobactam) demonstrate poor activity against class D \u03b2-lactamases. To overcome this challenge, we explored the abilities of \u03b2-lactamase inhibitors of the C-2- and C-3-substituted penicillin and cephalosporin sulfone families against OXA-1, extended-spectrum (OXA-10, OXA-14, and OXA-17), and carbapenemase-type (OXA-24\/40) class D \u03b2-lactamases. Three C-2-substituted penicillin sulfone compounds (JDB\/LN-1-255, JDB\/LN-III-26, and JDB\/ASR-II-292) showed low\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    values for the OXA-1 \u03b2-lactamase (0.70 \u00b1 0.14 \u2192 1.60 \u00b1 0.30 \u03bcM) and demonstrated significant\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    improvements compared to the C-3-substituted cephalosporin sulfone (JDB\/DVR-II-214), tazobactam, and clavulanic acid. The C-2-substituted penicillin sulfones JDB\/ASR-II-292 and JDB\/LN-1-255 also demonstrated low\n                    <jats:italic>\n                      K\n                      <jats:sub>i<\/jats:sub>\n                    <\/jats:italic>\n                    s for the OXA-10, -14, -17, and -24\/40 \u03b2-lactamases (0.20 \u00b1 0.04 \u2192 17 \u00b1 4 \u03bcM). Furthermore, JDB\/LN-1-255 displayed stoichiometric inactivation of OXA-1 (the turnover number, i.e., the partitioning of the initial enzyme inhibitor complex between hydrolysis and enzyme inactivation [\n                    <jats:italic>\n                      t\n                      <jats:sub>n<\/jats:sub>\n                    <\/jats:italic>\n                    ] = 0) and\n                    <jats:italic>\n                      t\n                      <jats:sub>n<\/jats:sub>\n                    <\/jats:italic>\n                    s ranging from 5 to 8 for the other OXA enzymes. Using mass spectroscopy to study the intermediates in the inactivation pathway, we determined that JDB\/LN-1-255 inhibited OXA \u03b2-lactamases by forming covalent adducts that do not fragment. On the basis of the substrate and inhibitor kinetics of OXA-1, we constructed a model showing that the C-3 carboxylate of JDB\/LN-1-255 interacts with Ser115 and Thr213, the R-2 group at C-2 fits between the space created by the long B9 and B10 \u03b2 strands, and stabilizing hydrophobic interactions are formed between the pyridyl ring of JDB\/LN-1-255 and Val116 and Leu161. By exploiting conserved structural and mechanistic features, JDB\/LN-1-255 is a promising lead compound in the quest for effective inhibitors of OXA-type \u03b2-lactamases.\n                  <\/jats:p>","DOI":"10.1128\/aac.00743-09","type":"journal-article","created":{"date-parts":[[2010,1,19]],"date-time":"2010-01-19T23:53:18Z","timestamp":1263945198000},"page":"1414-1424","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":38,"title":["Penicillin Sulfone Inhibitors of Class D \u03b2-Lactamases"],"prefix":"10.1128","volume":"54","author":[{"given":"Sarah M.","family":"Drawz","sequence":"first","affiliation":[{"name":"Departments of Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Bethel","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkata R.","family":"Doppalapudi","sequence":"additional","affiliation":[{"name":"Southern Methodist University, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjaneyulu","family":"Sheri","sequence":"additional","affiliation":[{"name":"Southern Methodist University, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sundar Ram Reddy","family":"Pagadala","sequence":"additional","affiliation":[{"name":"Southern Methodist University, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea M.","family":"Hujer","sequence":"additional","affiliation":[{"name":"Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion J.","family":"Skalweit","sequence":"additional","affiliation":[{"name":"Biochemistry"},{"name":"Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vernon E.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Biochemistry"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu G.","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Buynak","sequence":"additional","affiliation":[{"name":"Southern Methodist University, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Bonomo","sequence":"additional","affiliation":[{"name":"Pharmacology"},{"name":"Molecular Biology and Microbiology"},{"name":"Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio"},{"name":"Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.10.4410-4412.2005"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.2.583-588.2001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.11.158"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.186.3.595-600.2004"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.62.3.293-300.1951"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01677-07"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4838(01)00175-3"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.6.1556-1561.2000"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.14.4.933-951.2001"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi961044g"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dki425"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1086\/319610"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01009-09"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.6.1211"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.37.4.851"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867043364847"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(00)00098-6"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(99)00325-X"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-894X(02)00205-6"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi00604a025"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)84819-4"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4838(01)00133-9"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.6.1362"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.8.1881"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkf092"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2009.04.010"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.7.2380-2381.2003"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr030102i"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.6.2043-2048.2004"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.5.1973-1980.2005"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.241442898"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306059200"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568005033342181"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.1.268-273.2003"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.8.3198-3202.2005"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4838(01)00164-9"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00064a003"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi901416t"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj2920555"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00116-06"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi051719s"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.1.1"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja016736t"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(00)00534-7"},{"key":"e_1_3_2_46_2","doi-asserted-by":"crossref","first-page":"865","DOI":"10.2174\/1381612805666230112185101","volume":"5","year":"1999","unstructured":"Naas, T., and P. Nordmann. 1999. OXA-type \u03b2-lactamases. Curr. Pharm. Des.5:865-879.","journal-title":"Curr. Pharm. Des."},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja063715w"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/79688"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M806833200"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01464-06"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo060364v"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.2.447-453.2001"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.1.15-22.2004"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01512-08"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389201023378427"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2006.01456.x"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607557104"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501251200"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1110\/ps.0224303"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M603222200"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dki482"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.172.2.1137-1141.1990"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00743-09","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00743-09","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,29]],"date-time":"2023-05-29T13:36:36Z","timestamp":1685367396000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00743-09"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,4]]},"references-count":61,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2010,4]]}},"alternative-id":["10.1128\/AAC.00743-09"],"URL":"https:\/\/doi.org\/10.1128\/aac.00743-09","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,4]]},"assertion":[{"value":"2009-06-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2010-01-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2010-04-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}