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Analyzing the metabolic adaptation toward environmental stress conditions improves our understanding of its pathophysiology and its dependency on host-derived nutrients. In this study, extra- and intracellular metabolic profiles were evaluated to investigate the impact of antimicrobial compounds targeting different pathways of the metabolome of <jats:italic>S. pneumoniae<\/jats:italic> TIGR4<jats:italic>\u0394cps<\/jats:italic>. For the metabolomics approach, we analyzed the complex variety of metabolites by using <jats:sup>1<\/jats:sup>H NMR, HPLC-MS, and GC\u2013MS as different analytical techniques. Through this combination, we detected nearly 120 metabolites. For each antimicrobial compound, individual metabolic effects were detected that often comprised global biosynthetic pathways. Cefotaxime altered amino acids metabolism and carbon metabolism. The purine and pyrimidine metabolic pathways were mostly affected by moxifloxacin treatment. The combination of cefotaxime and azithromycin intensified the stress response compared with the use of the single antibiotic. However, we observed that three cell wall metabolites were altered only by treatment with the combination of the two antibiotics. Only moxifloxacin stress-induced alternation in CDP-ribitol concentration. Teixobactin-Arg10 resulted in global changes of pneumococcal metabolism. To meet the growing requirements for new antibiotics, our metabolomics approach has shown to be a promising complement to other OMICs investigations allowing insights into the mode of action of novel antimicrobial compounds.<\/jats:p>","DOI":"10.1038\/s41429-020-0296-3","type":"journal-article","created":{"date-parts":[[2020,3,24]],"date-time":"2020-03-24T11:06:01Z","timestamp":1585047961000},"page":"441-454","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Exploring metabolic adaptation of Streptococcus pneumoniae to antibiotics"],"prefix":"10.1038","volume":"73","author":[{"given":"Anne","family":"Leonard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"M\u00f6hlis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabea","family":"Schl\u00fcter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Lalk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Methling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,24]]},"reference":[{"key":"296_CR1","doi-asserted-by":"publisher","first-page":"130","DOI":"10.3810\/pgm.2010.03.2130","volume":"122","author":"TM File","year":"2010","unstructured":"File TM, Marrie TJ. 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