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This study aimed to assess through transcriptional profiling the stress response of <jats:italic>S<\/jats:italic>. <jats:italic>pneumoniae<\/jats:italic> strains after exposure to lethal penicillin concentrations to understand further the mode of action of penicillin. Two experimental designs (time-course and dose-response) were used for monitoring the effect of penicillin on the transcriptional profile. The expression of some genes previously shown to be modulated by penicillin was altered, including <jats:italic>ciaRH<\/jats:italic>, <jats:italic>pstS<\/jats:italic> and <jats:italic>clpL<\/jats:italic>. Genes of the <jats:italic>glnRA<\/jats:italic> and <jats:italic>glnPQ<\/jats:italic> operons were among the most downregulated genes in the three strains. These genes are involved in glutamine synthesis and uptake and LC-MS work confirmed that penicillin treatment increases the intracellular glutamine concentrations. Glutamine conferred a protective role against penicillin when added to the culture medium. Glutamine synthetase encoded by <jats:italic>glnA<\/jats:italic> catalyses the transformation of glutamate and ammonium into glutamine and its chemical inhibition by the inhibitor L-methionine sulfoximine is shown to sensitize <jats:italic>S<\/jats:italic>. <jats:italic>pneumoniae<\/jats:italic> to penicillin, including penicillin-resistant clinical isolates. In summary, a combination of RNA-seq and metabolomics revealed that penicillin interferes with glutamine metabolism suggesting strategies that could eventually be exploited for combination therapy or for reversal of resistance.<\/jats:p>","DOI":"10.1038\/s41598-017-15035-y","type":"journal-article","created":{"date-parts":[[2017,10,31]],"date-time":"2017-10-31T15:10:19Z","timestamp":1509462619000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Penicillin induces alterations in glutamine metabolism in Streptococcus pneumoniae"],"prefix":"10.1038","volume":"7","author":[{"given":"Jessica Y.","family":"El Khoury","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Boucher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michel G.","family":"Bergeron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Leprohon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Ouellette","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,11,6]]},"reference":[{"key":"15035_CR1","unstructured":"Pneumococcal Vaccines WHO Position Paper--2012. 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