{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T01:28:53Z","timestamp":1778722133016,"version":"3.51.4"},"reference-count":18,"publisher":"Proceedings of the National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2000,4,25]]},"abstract":"<jats:p>\n            Penicillin-resistant strains of\n            <jats:italic>Streptococcus pneumoniae<\/jats:italic>\n            contain low affinity penicillin-binding proteins and often also produce abnormal indirectly crosslinked cell walls. However the relationship between cell wall abnormality and penicillin resistance has remained obscure. We now show that the genome of\n            <jats:italic>S. pneumoniae<\/jats:italic>\n            contains an operon composed of two genes (\n            <jats:italic>murM<\/jats:italic>\n            and\n            <jats:italic>murN<\/jats:italic>\n            ) that encode enzymes involved with the biosynthesis of branched structured cell wall muropeptides. The sequences of\n            <jats:italic>murMN<\/jats:italic>\n            were compared in two strains: the penicillin-susceptible strain R36A producing the species-specific pneumococcal cell wall peptidoglycan in which branched stem peptides are rare, and the highly penicillin-resistant transformant strain Pen6, the cell wall of which is enriched for branched-structured stem peptides. The two strains carried different\n            <jats:italic>murM<\/jats:italic>\n            alleles:\n            <jats:italic>murM<\/jats:italic>\n            of the penicillin-resistant strain Pen6 had a \u201cmosaic\u201d structure encoding a protein that was only 86.5% identical to the product of\n            <jats:italic>murM<\/jats:italic>\n            identified in the isogenic penicillin-susceptible strain R36A. Mutants of R36A and Pen6 in which the\n            <jats:italic>murMN<\/jats:italic>\n            operon was interrupted by insertion-duplication mutagenesis produced peptidoglycan from which all branched muropeptide components were missing. The insertional mutant of Pen6 carried a\n            <jats:italic>pbp2x<\/jats:italic>\n            gene with the same \u201cmosaic\u201d sequence found in Pen6. On the other hand, inactivation of\n            <jats:italic>murMN<\/jats:italic>\n            in strain Pen6 and other resistant strains caused a virtually complete loss of penicillin resistance. Our observations indicate that the capacity to produce branched cell wall precursors plays a critical role in the expression of penicillin resistance in\n            <jats:italic>S. pneumoniae<\/jats:italic>\n            .\n          <\/jats:p>","DOI":"10.1073\/pnas.080067697","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T14:38:21Z","timestamp":1027694301000},"page":"4891-4896","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":164,"title":["Inhibition of the expression of penicillin resistance in\n            <i>Streptococcus pneumoniae<\/i>\n            by inactivation of cell wall muropeptide branching genes"],"prefix":"10.1073","volume":"97","author":[{"given":"Sergio R.","family":"Filipe","sequence":"first","affiliation":[{"name":"Laboratory of Microbiology, The Rockefeller University, New York, NY 10021; and Molecular Genetics Unit, Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica, Universidade Nova de Lisboa, 2780 Oeiras, Portugal"}]},{"given":"Alexander","family":"Tomasz","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, The Rockefeller University, New York, NY 10021; and Molecular Genetics Unit, Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica, Universidade Nova de Lisboa, 2780 Oeiras, Portugal"}]}],"member":"341","published-online":{"date-parts":[[2000,4,4]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1128\/AAC.17.3.434","volume":"17","author":"Zighelboim S","year":"1980","unstructured":"S Zighelboim, A Tomasz Antimicrob Agents Chemother 17, 434\u2013442 (1980).","journal-title":"Antimicrob Agents Chemother"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"5415","DOI":"10.1073\/pnas.87.14.5415","volume":"87","author":"Garcia-Bustos J","year":"1990","unstructured":"J Garcia-Bustos, A Tomasz Proc Natl Acad Sci USA 87, 5415\u20135419 (1990).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1128\/jb.170.5.2143-2147.1988","volume":"170","author":"Garcia-Bustos J F","year":"1988","unstructured":"J F Garcia-Bustos, B T Chait, A Tomasz J Bacteriol 170, 2143\u20132147 (1988).","journal-title":"J Bacteriol"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1128\/jb.178.1.168-174.1996","volume":"178","author":"Severin A","year":"1996","unstructured":"A Severin, A Tomasz J Bacteriol 178, 168\u2013174 (1996).","journal-title":"J Bacteriol"},{"key":"e_1_3_4_5_2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1084\/jem.79.2.137","volume":"79","author":"Avery O T","year":"1944","unstructured":"O T Avery, C M Macleod, M McCarty J Exp Med 79, 137\u2013157 (1944).","journal-title":"J Exp Med"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1089\/mdr.1998.4.325","volume":"4","author":"Corso A","year":"1998","unstructured":"A Corso, E P Severina, V F Petruk, Y R Mauriz, A Tomasz Microb Drug Resist 4, 325\u2013337 (1998).","journal-title":"Microb Drug Resist"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1093\/clinids\/15.1.112","volume":"15","author":"Munoz R","year":"1992","unstructured":"R Munoz, J M Musser, M Crain, D E Briles, A Marton, A J Parkinson, U Sorensen, A Tomasz Clin Infect Dis 15, 112\u2013118 (1992).","journal-title":"Clin Infect Dis"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1128\/jb.178.7.1788-1792.1996","volume":"178","author":"Severin A","year":"1996","unstructured":"A Severin, A M Figueiredo, A Tomasz J Bacteriol 178, 1788\u20131792 (1996).","journal-title":"J Bacteriol"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0378-1119(88)90489-1","volume":"64","author":"Chen J D","year":"1988","unstructured":"J D Chen, D A Morrison Gene 64, 155\u2013164 (1988).","journal-title":"Gene"},{"key":"e_1_3_4_10_2","volume-title":"Current Protocols in Molecular Biology","author":"Ausubel F M","year":"1996","unstructured":"F M Ausubel, R Brent, R E Kingston, D D Moore, J G Seidman, J A Smith, K Struhl Current Protocols in Molecular Biology (Wiley, New York, 1996)."},{"key":"e_1_3_4_11_2","volume-title":"Molecular Cloning: A Laboratory Manual","author":"Sambrook J E","year":"1989","unstructured":"J E Sambrook, I Fritsch, T Maniatis Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Lab. 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