{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:37:16Z","timestamp":1760146636613,"version":"build-2065373602"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T00:00:00Z","timestamp":1732147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro (FAPERJ), Brazil","award":["201.136\/2022","211.560\/2021","403236\/2023","88881.312022\/2018","001","PE00000007"],"award-info":[{"award-number":["201.136\/2022","211.560\/2021","403236\/2023","88881.312022\/2018","001","PE00000007"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq), Brazil","award":["201.136\/2022","211.560\/2021","403236\/2023","88881.312022\/2018","001","PE00000007"],"award-info":[{"award-number":["201.136\/2022","211.560\/2021","403236\/2023","88881.312022\/2018","001","PE00000007"]}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior (CAPES), Brazil","doi-asserted-by":"publisher","award":["201.136\/2022","211.560\/2021","403236\/2023","88881.312022\/2018","001","PE00000007"],"award-info":[{"award-number":["201.136\/2022","211.560\/2021","403236\/2023","88881.312022\/2018","001","PE00000007"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EU funding within the MUR PNRR Extended Partnership Initiative on Emerging Infectious Diseases","award":["201.136\/2022","211.560\/2021","403236\/2023","88881.312022\/2018","001","PE00000007"],"award-info":[{"award-number":["201.136\/2022","211.560\/2021","403236\/2023","88881.312022\/2018","001","PE00000007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Tuberculosis (TB) is one of the leading infectious causes of death worldwide, highlighting the importance of identifying new anti-TB agents. In previous research, our team identified antimycobacterial activity in Kielmeyera membranacea leaf extract; therefore, this study aims to conduct further exploration of its potential. Methods: Classical chromatography was applied for fractionation and spectrometric techniques were utilized for chemical characterization. For in vitro tests, samples were assessed against Mycobacterium tuberculosis and Mycobacterium marinum. The toxicity and efficacy of active samples were evaluated in vivo using different zebrafish models. Chemogenomics studies were applied to predict the isolated active compound\u2019s potential mode of action. Results: We performed fractionation of K. membranacea ethanolic extract (EE) and then its dichloromethane fraction (DCM), and the biflavonoid podocarpusflavone A (PCFA) was isolated and identified as a promising active compound. The EE and PCFA were found to be non-toxic to zebrafish larvae and were able to inhibit M. tuberculosis growth extracellularly. Additionally, PCFA demonstrated antimycobacterial activity within infected macrophages, especially when combined with isoniazid. In addition, the EE, DCM, and PCFA have shown the ability to inhibit M. marinum\u2019s growth during in vivo zebrafish larvae yolk infection. Notably, PCFA also effectively countered systemic infection established through the caudal vein, showing a similar inhibitory activity profile to rifampicin, both at 32 \u00b5M. A reduction in the transcriptional levels of pro-inflammatory cytokines confirmed the infection resolution. The protein tyrosine phosphatase B (PtpB) of M. tuberculosis, which inhibits the macrophage immune response, was predicted as a theoretical target of PCFA. This finding is in agreement with the higher activity observed for PCFA intracellularly and in vivo on zebrafish, compared with the direct action in M. tuberculosis. Conclusions: Here, we describe the discovery of PCFA as an intracellular inhibitor of M. tuberculosis and provide evidence of its in vivo efficacy and safety, encouraging its further development as a combination drug in novel therapeutic regimens for TB.<\/jats:p>","DOI":"10.3390\/ph17121560","type":"journal-article","created":{"date-parts":[[2024,11,21]],"date-time":"2024-11-21T04:46:11Z","timestamp":1732164371000},"page":"1560","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the Antimycobacterial Potential of Podocarpusflavone A from Kielmeyera membranacea: In Vitro and In Vivo Insights"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2117-5518","authenticated-orcid":false,"given":"Marlon Heggdorne de","family":"Araujo","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Produtos Bioativos (LPBio), Instituto de Ci\u00eancias Farmac\u00eauticas, Universidade Federal do Rio de Janeiro, Campus Maca\u00e9, Maca\u00e9 27930-560, RJ, Brazil"},{"name":"Department of Animal Sciences and Health, Institute of Biology (IBL), Leiden University, 2333 BE Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salom\u00e9","family":"Mu\u00f1oz S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences and Health, Institute of Biology (IBL), Leiden University, 2333 BE Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thatiana Lopes Bi\u00e1 Ventura","family":"Sim\u00e3o","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia do Reconhecer (LBR), Centro de Bioci\u00eancias e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Nowik","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences and Health, Institute of Biology (IBL), Leiden University, 2333 BE Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stella Schuenck","family":"Antunes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Produtos Bioativos (LPBio), Instituto de Ci\u00eancias Farmac\u00eauticas, Universidade Federal do Rio de Janeiro, Campus Maca\u00e9, Maca\u00e9 27930-560, RJ, Brazil"},{"name":"Laborat\u00f3rio Integrado de Computa\u00e7\u00e3o Cient\u00edfica (LICC), Universidade Federal do Rio de Janeiro, Campus Maca\u00e9, Maca\u00e9 27930-560, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1540-1440","authenticated-orcid":false,"given":"Shaft Corr\u00eaa","family":"Pinto","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Produtos Bioativos (LPBio), Instituto de Ci\u00eancias Farmac\u00eauticas, Universidade Federal do Rio de Janeiro, Campus Maca\u00e9, Maca\u00e9 27930-560, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1683-2102","authenticated-orcid":false,"given":"Davide","family":"Sorze","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Padova, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8310-9532","authenticated-orcid":false,"given":"Francesca","family":"Boldrin","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Padova, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0940-7336","authenticated-orcid":false,"given":"Riccardo","family":"Manganelli","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Padova, 35121 Padova, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nelilma","family":"Correia Romeiro","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio Integrado de Computa\u00e7\u00e3o Cient\u00edfica (LICC), Universidade Federal do Rio de Janeiro, Campus Maca\u00e9, Maca\u00e9 27930-560, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6726-273X","authenticated-orcid":false,"given":"Elena B.","family":"Lasunskaia","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia do Reconhecer (LBR), Centro de Bioci\u00eancias e Biotecnologia, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fons J.","family":"Verbeek","sequence":"additional","affiliation":[{"name":"Leiden Institute of Advanced Computer Science, Leiden University, 2333 CA Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-9501","authenticated-orcid":false,"given":"Herman P.","family":"Spaink","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences and Health, Institute of Biology (IBL), Leiden University, 2333 BE Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle Fraz\u00e3o","family":"Muzitano","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Produtos Bioativos (LPBio), Instituto de Ci\u00eancias Farmac\u00eauticas, Universidade Federal do Rio de Janeiro, Campus Maca\u00e9, Maca\u00e9 27930-560, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,21]]},"reference":[{"key":"ref_1","unstructured":"WHO, World Health Organization (2024, November 05). Global Tuberculosis Report. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240101531."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.drudis.2016.11.015","article-title":"Recent developments in natural product-based drug discovery for tuberculosis","volume":"22","author":"Dong","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sharifi-Rad, M., Lankatillake, C., Dias, D.A., Docea, A.O., Mahomoodally, M.F., Lobine, D., Chazot, P.L., Kurt, B., Boyunegmez, T.T., and Catarina, M.A. (2020). Impact of Natural Compounds on Neurodegenerative Disorders: From Preclinical to Pharmacotherapeutics. J. Clin. Med., 9.","DOI":"10.3390\/jcm9041061"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sousa, Z.L., de Oliveira, F.F., da Concei\u00e7\u00e3o, A.O., Silva, L.A., Rossi, M.H., Santos, J.D.S., and Andrioli, J.L. (2012). Biological activities of extracts from Chenopodium ambrosioides Lineu and Kielmeyera neglecta Saddi. Ann. Clin. Microbiol. Antimicrob., 11.","DOI":"10.1186\/1476-0711-11-20"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1021\/acs.jnatprod.5b00858","article-title":"Antistaphylococcal Prenylated Acylphoroglucinol and Xanthones from Kielmeyera variabilis","volume":"79","author":"Coqueiro","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"842047","DOI":"10.1155\/2015\/842047","article-title":"Chemical Constituents and Evaluation of Antimicrobial and Cytotoxic Activities of Kielmeyera coriacea Mart. & Zucc. Essential Oils","volume":"2015","author":"Martins","year":"2015","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/S0031-9422(97)00731-0","article-title":"Xanthones, triterpenes and a biphenyl from Kielmeyera coriacea","volume":"47","author":"Cortez","year":"1998","journal-title":"Phytochemistry"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Justino, A.B., Santana, E.C., Franco, R.R., Queiroz, J.S., Silva, H.C.G., de Lima, J.P.J., Saraiva, A.L., Martins, M.M., Lemos de Morais, S.A., and de Oliveira, A. (2021). Antioxidant compounds of Kielmeyera coriacea Mart. with \u03b1-amylase, lipase and advanced glycation end-product inhibitory activities. J. Pharm. Biomed. Anal., 206.","DOI":"10.1016\/j.jpba.2021.114387"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"104836","DOI":"10.1016\/j.fitote.2021.104836","article-title":"Prenylated 4-phenylcoumarins and 4-alkylcoumarins from Kielmeyera argentea and their cytotoxic activity","volume":"149","author":"Boness","year":"2021","journal-title":"Fitoterapia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/j.phymed.2011.08.067","article-title":"Assessment of anxiolytic and panicolytic effects of dichloromethane fraction from stems of Kielmeyera coriacea","volume":"19","author":"Biesdorf","year":"2012","journal-title":"Phytomedicine"},{"key":"ref_11","first-page":"429","article-title":"Antitumor activity of kielmeyera coriacea leaf constituents in experimental melanoma, tested in vitro and in vivo in syngeneic mice","volume":"4","author":"Figueiredo","year":"2014","journal-title":"Adv. Pharm. Bull."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1590\/S2175-78602013000100007","article-title":"Caracteriza\u00e7\u00e3o dos frutos, sementes e pl\u00e2ntulas de esp\u00e9cies de Clusiaceae das restingas do Rio de Janeiro","volume":"64","author":"Correia","year":"2013","journal-title":"Rodrigu\u00e9sia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e01152019","DOI":"10.1590\/2175-7860202172040","article-title":"Anti-mycobacterial and anti-inflammatory activity of Restinga plants: A dual approach in searching for new drugs to treat severe tuberculosis","volume":"72","author":"Araujo","year":"2021","journal-title":"Rodriguesia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/bdrc.20206","article-title":"Zebrafish embryos and larvae: A new generation of disease models and drug screens","volume":"93","author":"Ali","year":"2011","journal-title":"Birth Defects Res. C. Embryo Today"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1242\/dmm.015594","article-title":"Macrophage-pathogen interactions in infectious diseases: New therapeutic insights from the zebrafish host model","volume":"7","author":"Torraca","year":"2014","journal-title":"Dis. Mod. Mech."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1038\/nprot.2013.068","article-title":"Evaluation of the pathogenesis and treatment of Mycobacterium marinum infection in zebrafish","volume":"8","author":"Takaki","year":"2013","journal-title":"Nat. Prot."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.celrep.2012.06.008","article-title":"An in vivo platform for rapid high-throughput antitubercular drug discovery","volume":"26","author":"Takaki","year":"2012","journal-title":"Cell Rep."},{"key":"ref_18","first-page":"191","article-title":"Basement Membrane Diseases in Zebrafish. In: Detrich, H.W., Westerfield, M., Zon, L.I. (Org.). Methods in Cell Biology: The Zebrafish, Disease Models and Chemical Screens","volume":"105","author":"Feitosa","year":"2011","journal-title":"Elsevier Corp."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.3390\/molecules18022376","article-title":"Free Radical Scavenging Activity of Kielmeyera variabilis (Clusiaceae)","volume":"18","author":"Coqueiro","year":"2013","journal-title":"Molecules"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S2225-4110(16)30103-1","article-title":"Naturally Occurring Cytotoxic [3\u2032\u21928\u2033]-Biflavonoids from Podocarpus nakaii","volume":"2","author":"Yeh","year":"2012","journal-title":"J. Trad. Complem. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yu, S., Yan, H., Zhang, L., Shan, M., Chen, P., Ding, A., and Li, S.F. (2017). A Review on the Phytochemistry, Pharmacology, and Pharmacokinetics of Amentoflavone, a Naturally-Occurring Biflavonoid. Molecules, 22.","DOI":"10.3390\/molecules22020299"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lim, D.J., Song, J.S., Lee, B.H., Son, Y.K., and Kim, Y. (2023). Qualitative and Quantitative Analysis of the Major Bioactive Components of Juniperus chinensis L. Using LC-QTOF-MS and LC-MS\/MS and Investigation of Antibacterial Activity against Pathogenic Bacteria. Molecules, 28.","DOI":"10.3390\/molecules28093937"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.jdermsci.2020.10.008","article-title":"Podocarpusflavone A inhibits cell growth of skin cutaneous melanoma by suppressing STAT3 signaling","volume":"100","author":"Meng","year":"2020","journal-title":"J. Dermatol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1055\/s-2000-8598","article-title":"Bioactive compounds from Celaenodendron mexicanum","volume":"66","author":"Camacho","year":"2000","journal-title":"Planta Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1055\/s-0031-1298355","article-title":"Biflavonoids of Dacrydium balansae with potent inhibitory activity on dengue 2 NS5 polymerase","volume":"78","author":"Coulerie","year":"2012","journal-title":"Planta Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12048","DOI":"10.1080\/07391102.2021.1969285","article-title":"MD simulation and MM\/PBSA identifies phytochemicals as bifunctional inhibitors of SARS-CoV-2","volume":"40","author":"Sharma","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_27","first-page":"935","article-title":"Tirucallane glycoside from the leaves of Antidesma bunius and inhibitory NO production in BV2 cells and RAW264.7 macrophages","volume":"11","author":"Trang","year":"2016","journal-title":"Nat. Prod. Commun."},{"key":"ref_28","first-page":"410","article-title":"Redox-active biflavonoids from Garcinia brasiliensis as inhibitors of neutrophil oxidative burst and human erythrocyte membrane damage","volume":"4","author":"Zeraik","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4302","DOI":"10.1016\/j.ejmech.2011.06.037","article-title":"Novel aryloxy azolyl chalcones with potent activity against Mycobacterium tuberculosis H37Rv","volume":"46","author":"Marrapu","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"239","DOI":"10.5588\/ijtld.17.0660","article-title":"Principles for constructing a tuberculosis treatment regimen: The role and definition of core and companion drugs","volume":"22","author":"Decroo","year":"2018","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sankar, J., Chauhan, A., Singh, R., and Mahajan, D. (2024). Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1441147"},{"key":"ref_32","first-page":"196","article-title":"Is the fish embryo toxicity test (FET) with the zebrafish (Danio rerio) a potential alternative for the fish acute toxicity test?","volume":"149","author":"Lammer","year":"2009","journal-title":"Comp. Biochem. Physiol. Part. C"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1016\/j.str.2007.03.003","article-title":"Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB","volume":"15","author":"Grundner","year":"2007","journal-title":"Structure"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Mascarello, A., Mori, M., Chiaradia-Delatorre, L.D., Menegatti, A.C.L., Monache, F.D., Ferrari, F., Yunes, R.A., Nunes, R.J., Terenzi, H., and Botta, B. (2013). Discovery of Mycobacterium tuberculosis protein tyrosine phosphatase B (PtpB) inhibitors from natural products. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077081"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Kuban-Jankowska, A., Kostrzewa, T., and Gorska-Ponikowska, M. (2022). Bacterial protein tyrosine phosphatases as possible targets for antimicrobial therapies in response to antibiotic resistance. Antioxidants, 11.","DOI":"10.3390\/antiox11122397"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.tim.2012.09.002","article-title":"Mycobacterium tuberculosis-secreted phosphatases: From pathogenesis to targets for TB drug development","volume":"21","author":"Wong","year":"2013","journal-title":"Trends Microbiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"eabq0132","DOI":"10.1126\/science.abq0132","article-title":"A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin","volume":"378","author":"Chai","year":"2022","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"14747","DOI":"10.1021\/jacs.8b08070","article-title":"Compound molecular logic in accessing the active site of Mycobacterium tuberculosis protein tyrosine phosphatase B","volume":"140","author":"Morrell","year":"2018","journal-title":"J. Am. Chem. Soc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4573","DOI":"10.1073\/pnas.0909133107","article-title":"Targeting Mycobacterium protein tyrosine phosphatase B for antituberculosis agents","volume":"107","author":"Zhou","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"105166","DOI":"10.1016\/j.meegid.2021.105166","article-title":"Cytokine storm in tuberculosis and IL-6 involvement","volume":"97","author":"Boni","year":"2022","journal-title":"Infect. Genet. Evol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.bmcl.2019.04.034","article-title":"Dual-targeting GroEL\/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections","volume":"29","author":"Washburn","year":"2019","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.immuni.2008.06.011","article-title":"Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death","volume":"29","author":"Clay","year":"2008","journal-title":"Immunity"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.molimm.2010.12.012","article-title":"Discovery of zebrafish (Danio rerio) interleukin-23 alpha (IL-23\u03b1) chain, a subunit important for the formation of IL-23, a cytokine involved in the development of Th17 cells and inflammation","volume":"48","author":"Holt","year":"2011","journal-title":"Mol. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Vemula, M.H., Medisetti, R., Ganji, R., Jakkala, K., Sankati, S., Chatti, K., and Banerjee, S. (2016). Mycobacterium tuberculosis Zinc Metalloprotease-1 Assists Mycobacterial Dissemination in Zebrafish. Front. Microbiol., 29.","DOI":"10.3389\/fmicb.2016.01347"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/j.cell.2019.08.004","article-title":"TNF Induces Pathogenic Programmed Macrophage Necrosis in Tuberculosis through a Mitochondrial-Lysosomal-Endoplasmic Reticulum Circuit","volume":"178","author":"Roca","year":"2019","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Harjula, S.E., Ojanen, M.J.T., Taavitsainen, S., Nykter, M., and R\u00e4met, M. (2018). Interleukin 10 mutant zebrafish have an enhanced interferon-gamma response and improved survival against a Mycobacterium marinum infection. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-28511-w"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s00281-015-0522-4","article-title":"Protection and pathology in TB: Learning from the zebrafish model","volume":"38","author":"Meijer","year":"2016","journal-title":"Semin. Immunopathol."},{"key":"ref_48","first-page":"253","article-title":"The CXCR3-CXCL11 signaling axis mediates macrophage recruitment and dissemination of mycobacterial infection","volume":"8","author":"Torraca","year":"2015","journal-title":"Dis. Mod. Mech."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1111\/mmi.14838","article-title":"A fresh look at mycobacterial pathogenicity with the zebrafish host model","volume":"117","author":"Varela","year":"2022","journal-title":"Mol. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1128\/AAC.44.11.3133-3136.2000","article-title":"Antibiotic susceptibility pattern of Mycobacterium marinum","volume":"44","author":"Aubry","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1128\/jcm.33.7.1842-1846.1995","article-title":"Determination of MICs for Mycobacterium avium-M. Intracellular complex in liquid medium by a colorimetric method","volume":"33","author":"Gupta","year":"1995","journal-title":"J. Clin. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1046\/j.1365-2958.2001.02525.x","article-title":"The Mycobacterium tuberculosis ECF sigma factor sE: Role in global gene expression and survival in macrophages","volume":"41","author":"Manganelli","year":"2001","journal-title":"Mol. Microbiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e00439-e20","DOI":"10.1128\/JB.00439-20","article-title":"The Phosphatidyl-myo-Inositol Dimannoside Acyltransferase PatA Is Essential for Mycobacterium tuberculosis Growth In Vitro and In Vivo","volume":"203","author":"Boldrin","year":"2021","journal-title":"J. Bacteriol."},{"key":"ref_54","unstructured":"Westerfield, M. (2000). The Zebrafish Book: A Guide for the Laboratory Use of Zebrafish (Danio Rerio), University Oregon Press. [4th ed.]."},{"key":"ref_55","unstructured":"OECD (2013). Test No. 236: Fish Embryo Acute Toxicity (FET) Test. OECD Guidelines for the Testing of Chemicals, Section 2, OECD iLibrary."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13321-015-0098-y","article-title":"Target prediction utilizing negative bioactivity data covering large chemical space","volume":"7","author":"Mervin","year":"2015","journal-title":"J. Cheminformatics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1093\/bioinformatics\/btx525","article-title":"Orthologue chemical space and its influence on target prediction","volume":"34","author":"Mervin","year":"2018","journal-title":"Bioinformatics"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"W665","DOI":"10.1093\/nar\/gkh381","article-title":"PDB2PQR: An automated pipeline for the setup of Poisson\u2013Boltzmann electrostatics calculations","volume":"32","author":"Todd","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_60","unstructured":"Hehre, W.J. (2003). A Guide to Molecular Mechanics and Quantum Chemical Calculations, Wavefunction, Inc."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/12\/1560\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:36:34Z","timestamp":1760114194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/12\/1560"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,21]]},"references-count":60,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ph17121560"],"URL":"https:\/\/doi.org\/10.3390\/ph17121560","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2024,11,21]]}}}