{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:04:59Z","timestamp":1791273899731,"version":"4.1.0"},"reference-count":31,"publisher":"American Chemical Society (ACS)","issue":"22","license":[{"start":{"date-parts":[[2015,5,20]],"date-time":"2015-05-20T00:00:00Z","timestamp":1432080000000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The genome of Mycobacterium tuberculosis contains a gene, blaC, which encodes a highly active \u03b2-lactamase (BlaC). We have previously shown that BlaC has an extremely broad spectrum of activity against penicillins and cephalosporins but weak activity against newer carbapenems. We have shown that carbapenems such as meropenem, doripenem, and ertapenem react with the enzyme to form enzyme\u2013drug covalent complexes that are hydrolyzed extremely slowly. In the current study, we have determined apparent Km and kcat values of 0.8 \u03bcM and 0.03 min\u20131, respectively, for tebipenem, a novel carbapenem whose prodrug form, the pivalyl ester, is orally available. Tebipenem exhibits slow tight-binding inhibition at low micromolar concentrations versus the chromogenic substrate nitrocefin. FT-ICR mass spectrometry demonstrated that the tebipenem acyl\u2013enzyme complex remains stable for greater than 90 min and exists as mixture of the covalently bound drug and the bound retro-aldol cleavage product. We have also determined the high-resolution crystal structures of the BlaC\u2013tebipenem covalent acylated adduct (1.9 \u00c5) with wild-type BlaC and the BlaC\u2013tebipenem Michaelis\u2013Menten complex (1.75 \u00c5) with the K73A BlaC variant. These structures are compared to each other and to other carbapenem\u2013BlaC structures.<\/jats:p>","DOI":"10.1021\/bi500339j","type":"journal-article","created":{"date-parts":[[2014,5,20]],"date-time":"2014-05-20T06:06:12Z","timestamp":1400565972000},"page":"3671-3678","source":"Crossref","is-referenced-by-count":42,"title":["Tebipenem, a New Carbapenem Antibiotic, Is a Slow\nSubstrate That Inhibits the \u03b2-Lactamase from\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1021","volume":"53","author":[{"given":"Saugata","family":"Hazra","sequence":"first","affiliation":[{"name":"Albert Einstein College of Medicine , , 1300 Morris Park Avenue , , ,","place":["Bronx, New York, United States, 10461"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Xu","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine , , 1300 Morris Park Avenue , , ,","place":["Bronx, New York, United States, 10461"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Blanchard","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine , , 1300 Morris Park Avenue , , ,","place":["Bronx, New York, United States, 10461"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,5,20]]},"reference":[{"key":"2026090316180628500_cit1","first-page":"516","volume-title":"Robbins\nBasic Pathology","author":"Kumar","year":"2007","edition":"8"},{"key":"2026090316180628500_cit2","doi-asserted-by":"crossref","first-page":"12","DOI":"10.18773\/austprescr.2010.005","article-title":"Testing for\ntuberculosis","volume":"33","author":"Konstantinos","year":"2010","journal-title":"Australian Prescriber"},{"key":"2026090316180628500_cit3","unstructured":"(2011)  The sixteenth global report\non tuberculosis, World Health Organization, Geneva, Switzerland, http:\/\/www.who.int\/tb\/publications\/global_report\/2011\/gtbr11_full.pdf."},{"key":"2026090316180628500_cit4","unstructured":"(2010)  Multidrug and extensively drug-resistant\nTB\n(M\/XDR-TB): 2010 global report on surveillance and response, World Health Organization, Geneva, Switzerland, http:\/\/whqlibdoc.who.int\/publications\/2010\/9789241599191_eng.pdf."},{"key":"2026090316180628500_cit5","first-page":"310","article-title":"Progress\nin global tuberculosis control\n1995\u20131996, with emphasis on 22 high-incidence countries. 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Rev."},{"key":"2026090316180628500_cit14","doi-asserted-by":"crossref","first-page":"4551","DOI":"10.1021\/bi300508r","article-title":"NXL104 irreversibly inhibits the\n\u03b2-lactamase from Mycobacterium tuberculosis","volume":"51","author":"Xu","year":"2012","journal-title":"Biochemistry"},{"key":"2026090316180628500_cit15","doi-asserted-by":"crossref","first-page":"11998","DOI":"10.1021\/bi701506h","article-title":"Irreversible inhibition of the Mycobacterium tuberculosis \u03b2-lactamase by clavulanate","volume":"46","author":"Hugonnet","year":"2007","journal-title":"Biochemistry"},{"key":"2026090316180628500_cit16","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1126\/science.1167498","article-title":"Meropenem-clavulanate is effective against extensively\ndrug-resistant Mycobacterium tuberculosis","volume":"323","author":"Hugonnet","year":"2009","journal-title":"Science"},{"key":"2026090316180628500_cit17","doi-asserted-by":"crossref","first-page":"3766","DOI":"10.1021\/bi100232q","article-title":"Biochemical and structural characterization of Mycobacterium tuberculosis \u03b2-lactamase with the carbapenems\nertapenem and doripenem","volume":"49","author":"Tremblay","year":"2010","journal-title":"Biochemistry"},{"key":"2026090316180628500_cit18","doi-asserted-by":"crossref","first-page":"564","DOI":"10.2174\/092986709787458498","article-title":"Current status\nof newer carbapenems","volume":"16","author":"Bassetti","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"2026090316180628500_cit19","doi-asserted-by":"crossref","first-page":"434","DOI":"10.2133\/dmpk.23.434","article-title":"Population pharmacokinetics\nof tebipenem\npivoxil (ME1211), a novel oral carbapenem antibiotic, in pediatric\npatients with otolaryngological infection or pneumonia","volume":"23","author":"Sato","year":"2008","journal-title":"Drug Metab. Pharmacokinet."},{"key":"2026090316180628500_cit20","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1128\/AAC.43.8.2010","article-title":"In vitro antibacterial\nactivity of LJC 11,036, an active metabolite of L-084, a new oral\ncarbapenem antibiotic with potent antipneumococcal activity","volume":"43","author":"Hikida","year":"1999","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026090316180628500_cit21","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1021\/mp100130b","article-title":"Intestinal\nabsorption mechanism of tebipenem pivoxil, a novel oral carbapenem:\ninvolvement of human OATP family in apical membrane transport","volume":"7","author":"Kato","year":"2010","journal-title":"Mol. Pharmaceutics"},{"key":"2026090316180628500_cit22","first-page":"214","article-title":"Pharmacokinetics of\ntebipenem pivoxil, a novel oral carbapenem antibiotic, in experimental\nanimals","volume":"62","author":"Kijima","year":"2009","journal-title":"Jpn. J. Antibiot."},{"key":"2026090316180628500_cit23","doi-asserted-by":"crossref","first-page":"9685","DOI":"10.1021\/bi1015088","article-title":"Structures\nof the Michaelis complex (1.2 \u00c5) and\nthe covalent acyl intermediate (2.0 \u00c5) of cefamandole bound to\nthe active site of the Mycobacterium tuberculosis \u03b2-lactamase K73A and E166A mutants","volume":"49","author":"Tremblay","year":"2010","journal-title":"Biochemistry"},{"key":"2026090316180628500_cit24","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0076-6879(97)76066-X","article-title":"Processing\nof X-ray diffraction data collected in oscillation mode","volume":"276","author":"Otwinowski","year":"1997","journal-title":"Methods Enzymol."},{"key":"2026090316180628500_cit25","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1107\/S0907444903008126","article-title":"A graphical user interface\nto the CCP4 program suite","volume":"59","author":"Potterton","year":"2003","journal-title":"Acta Crystallogr.,\nSect. 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