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A swift and precise diagnosis is essential to forestall its transmission, for which the discovery of effective diagnostic biomarkers is crucial. In this study, we aimed to discover molecular biomarkers for the early diagnosis of tuberculosis. Two independent cohorts comprising 29 and 34 subjects were assayed by proteomics, and 49 were included for metabolomic analysis. All subjects were arranged into three experimental groups\u2014healthy controls (controls), latent TB infection (LTBI), and TB patients. LC-MS\/MS blood serum protein and metabolite levels were submitted to univariate, multivariate, and ROC analysis. From the 149 proteins quantified in the discovery set, 25 were found to be differentially abundant between controls and TB patients. The AUC, specificity, and sensitivity, determined by ROC statistical analysis of the model composed of four of these proteins considering both proteomic sets, were 0.96, 93%, and 91%, respectively. The five metabolites (9-methyluric acid, indole-3-lactic acid, trans-3-indoleacrylic acid, hexanoylglycine, and N-acetyl-L-leucine) that better discriminate the control and TB patient groups (VIP &gt; 1.75) from a total of 92 metabolites quantified in both ionization modes were submitted to ROC analysis. An AUC = 1 was determined, with all samples being correctly assigned to the respective experimental group. An integrated ROC analysis enrolling one protein and four metabolites was also performed for the common control and TB patients in the proteomic and metabolomic groups. This combined signature correctly assigned the 12 controls and 12 patients used only for prediction (AUC = 1, specificity = 100%, and sensitivity = 100%). This multiomics approach revealed a biomarker signature for tuberculosis diagnosis that could be potentially used for developing a point-of-care diagnosis clinical test.<\/jats:p>","DOI":"10.3390\/ijms232213733","type":"journal-article","created":{"date-parts":[[2022,11,9]],"date-time":"2022-11-09T02:34:52Z","timestamp":1667961292000},"page":"13733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Mass Spectrometry-Based Proteomic and Metabolomic Profiling of Serum Samples for Discovery and Validation of Tuberculosis Diagnostic Biomarker Signature"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5579-2629","authenticated-orcid":false,"given":"Ana Filipa","family":"Fernandes","sequence":"first","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal"}]},{"given":"Lu\u00eds Gafeira","family":"Gon\u00e7alves","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal"}]},{"given":"Maria","family":"Bento","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2180-3518","authenticated-orcid":false,"given":"Sandra I.","family":"Anjo","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3004-504 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-4042","authenticated-orcid":false,"given":"Bruno","family":"Manadas","sequence":"additional","affiliation":[{"name":"CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"CIBB\u2014Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-504 Coimbra, Portugal"},{"name":"III Institute for Interdisciplinary Research, University of Coimbra (IIIUC), 3004-504 Coimbra, Portugal"}]},{"given":"Clara","family":"Barroso","sequence":"additional","affiliation":[{"name":"CDP Almada-Seixal, ARSLVT, 2805-021 Almada, Portugal"}]},{"given":"Miguel","family":"Villar","sequence":"additional","affiliation":[{"name":"CDP Venda Nova, ARSLVT, 2700-220 Amadora, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2184-5136","authenticated-orcid":false,"given":"Rita","family":"Macedo","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Sa\u00fade Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal"}]},{"given":"Maria Jo\u00e3o","family":"Sim\u00f5es","sequence":"additional","affiliation":[{"name":"Instituto Nacional de Sa\u00fade Dr. Ricardo Jorge, 1649-016 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6143-4203","authenticated-orcid":false,"given":"Ana Varela","family":"Coelho","sequence":"additional","affiliation":[{"name":"Instituto de Tecnologia Qu\u00edmica e Biol\u00f3gica Ant\u00f3nio Xavier, Universidade Nova de Lisboa, 2780-157 Oeiras, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,8]]},"reference":[{"key":"ref_1","unstructured":"WHO (2019). 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