{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:31:15Z","timestamp":1787027475890,"version":"build-2736575974"},"reference-count":48,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T00:00:00Z","timestamp":1679961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq)","award":["141341\/2020-3"],"award-info":[{"award-number":["141341\/2020-3"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq)","award":["2002\/2022"],"award-info":[{"award-number":["2002\/2022"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq)","award":["88887.513720\/2020-00"],"award-info":[{"award-number":["88887.513720\/2020-00"]}]},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq)","award":["IMP-CIAS-2924"],"award-info":[{"award-number":["IMP-CIAS-2924"]}]},{"name":"Paraiba State Research Foundation (FAPESQ)","award":["141341\/2020-3"],"award-info":[{"award-number":["141341\/2020-3"]}]},{"name":"Paraiba State Research Foundation (FAPESQ)","award":["2002\/2022"],"award-info":[{"award-number":["2002\/2022"]}]},{"name":"Paraiba State Research Foundation (FAPESQ)","award":["88887.513720\/2020-00"],"award-info":[{"award-number":["88887.513720\/2020-00"]}]},{"name":"Paraiba State Research Foundation (FAPESQ)","award":["IMP-CIAS-2924"],"award-info":[{"award-number":["IMP-CIAS-2924"]}]},{"name":"Coordination of Improvement of Higher Education Personnel\u2014Brazil (CAPES)","award":["141341\/2020-3"],"award-info":[{"award-number":["141341\/2020-3"]}]},{"name":"Coordination of Improvement of Higher Education Personnel\u2014Brazil (CAPES)","award":["2002\/2022"],"award-info":[{"award-number":["2002\/2022"]}]},{"name":"Coordination of Improvement of Higher Education Personnel\u2014Brazil (CAPES)","award":["88887.513720\/2020-00"],"award-info":[{"award-number":["88887.513720\/2020-00"]}]},{"name":"Coordination of Improvement of Higher Education Personnel\u2014Brazil (CAPES)","award":["IMP-CIAS-2924"],"award-info":[{"award-number":["IMP-CIAS-2924"]}]},{"name":"Universidad Militar Nueva Granada (UMNG)","award":["141341\/2020-3"],"award-info":[{"award-number":["141341\/2020-3"]}]},{"name":"Universidad Militar Nueva Granada (UMNG)","award":["2002\/2022"],"award-info":[{"award-number":["2002\/2022"]}]},{"name":"Universidad Militar Nueva Granada (UMNG)","award":["88887.513720\/2020-00"],"award-info":[{"award-number":["88887.513720\/2020-00"]}]},{"name":"Universidad Militar Nueva Granada (UMNG)","award":["IMP-CIAS-2924"],"award-info":[{"award-number":["IMP-CIAS-2924"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>The bifunctional enzyme Dihydrofolate reductase-thymidylate synthase (DHFR-TS) plays a crucial role in the survival of the Leishmania parasite, as folates are essential cofactors for purine and pyrimidine nucleotide biosynthesis. However, DHFR inhibitors are largely ineffective in controlling trypanosomatid infections, largely due to the presence of Pteridine reductase 1 (PTR1). Therefore, the search for structures with dual inhibitory activity against PTR1\/DHFR-TS is crucial in the development of new anti-Leishmania chemotherapies. In this research, using the Leishmania major DHFR-TS recombinant protein, enzymatic inhibitory assays were performed on four kauranes and two derivatives that had been previously tested against LmPTR1. The structure 302 (6.3 \u00b5M) and its derivative 302a (4.5 \u00b5M) showed the lowest IC50 values among the evaluated molecules. To evaluate the mechanism of action of these structures, molecular docking calculations and molecular dynamics simulations were performed using a DHFR-TS hybrid model. Results showed that hydrogen bond interactions are critical for the inhibitory activity against LmDHFR-TS, as well as the presence of the p-hydroxyl group of the phenylpropanoid moiety of 302a. Finally, additional computational studies were performed on DHFR-TS structures from Leishmania species that cause cutaneous and mucocutaneous leishmaniasis in the New World (L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes in these species. It was demonstrated that structures 302 and 302a are multi-Leishmania species compounds with dual DHFR-TS\/PTR1 inhibitory activity.<\/jats:p>","DOI":"10.3390\/antibiotics12040663","type":"journal-article","created":{"date-parts":[[2023,3,28]],"date-time":"2023-03-28T06:15:15Z","timestamp":1679984115000},"page":"663","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Kaurane-Type Diterpenoids as Potential Inhibitors of Dihydrofolate Reductase-Thymidylate Synthase in New World Leishmania Species"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6220-9091","authenticated-orcid":false,"given":"Chonny","family":"Herrera-Acevedo","sequence":"first","affiliation":[{"name":"Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"},{"name":"Department of Chemical Engineering, Universidad ECCI, Bogot\u00e1, Distrito Capital 111311, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata Priscila Barros","family":"de Menezes","sequence":"additional","affiliation":[{"name":"Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nat\u00e1lia Ferreira","family":"de Sousa","sequence":"additional","affiliation":[{"name":"Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1866-4107","authenticated-orcid":false,"given":"Luciana","family":"Scotti","sequence":"additional","affiliation":[{"name":"Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4863-8057","authenticated-orcid":false,"given":"Marcus Tullius","family":"Scotti","sequence":"additional","affiliation":[{"name":"Post-Graduate Program in Natural and Synthetic Bioactive Products, Federal University of Para\u00edba, Jo\u00e3o Pessoa 58051-900, PB, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3553-9749","authenticated-orcid":false,"given":"Ericsson","family":"Coy-Barrera","sequence":"additional","affiliation":[{"name":"Bioorganic Chemistry Laboratory, Facultad de Ciencias B\u00e1sicas y Aplicadas, Universidad Militar Nueva Granada, Cajic\u00e1 250247, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Soni, M., and Pratap, J.V. (2022). Development of Novel Anti-Leishmanials: The Case for Structure-Based Approaches. Pathogens, 11.","DOI":"10.3390\/pathogens11080950"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"102622","DOI":"10.1016\/j.parint.2022.102622","article-title":"Evaluation of target-specific natural compounds for drug discovery against leishmaniasis","volume":"91","author":"Gouri","year":"2022","journal-title":"Parasitol. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e24599","DOI":"10.1002\/jcla.24599","article-title":"Global distribution of treatment resistance gene markers for leishmaniasis","volume":"36","author":"Salari","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.1007\/s00436-021-07139-2","article-title":"Leishmaniasis: Where are we and where are we heading?","volume":"120","author":"Sasidharan","year":"2021","journal-title":"Parasitol. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109649","DOI":"10.1016\/j.intimp.2022.109649","article-title":"Emerging strategies and challenges of molecular therapeutics in antileishmanial drug development","volume":"115","author":"Gupta","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fr\u00e9zard, F., Aguiar, M.M.G., Ferreira, L.A.M., Ramos, G.S., Santos, T.T., Borges, G.S.M., Vallejos, V.M.R., and De Morais, H.L.O. (2023). Liposomal Amphotericin B for Treatment of Leishmaniasis: From the Identification of Critical Physicochemical Attributes to the Design of Effective Topical and Oral Formulations. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15010099"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1017\/S0031182016002523","article-title":"Chemotherapy of leishmaniasis: Present challenges","volume":"145","author":"Uliana","year":"2018","journal-title":"Parasitology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"622286","DOI":"10.3389\/fchem.2021.622286","article-title":"An Overview on the Therapeutics of Neglected Infectious Diseases\u2014Leishmaniasis and Chagas Diseases","volume":"9","author":"Brindha","year":"2021","journal-title":"Front. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1042\/bse0510063","article-title":"Folate metabolic pathways in Leishmania","volume":"51","author":"Vickers","year":"2011","journal-title":"Essays Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0925-4439(02)00088-1","article-title":"Inhibitors of dihydrofolate reductase in leishmania and trypanosomes","volume":"1587","author":"Gilbert","year":"2002","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/0014-4894(90)90119-W","article-title":"Thymidylate synthase-dihydrofolate reductase in protozoa","volume":"70","author":"Ivanetich","year":"1990","journal-title":"Exp. Parasitol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"6659","DOI":"10.1007\/s11033-022-07266-8","article-title":"Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: Successful targets against some infectious diseases","volume":"49","author":"Shamshad","year":"2022","journal-title":"Mol. Biol. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10429","DOI":"10.1074\/jbc.M110.209593","article-title":"Dissecting the metabolic roles of pteridine reductase 1 in Trypanosoma brucei and Leishmania major","volume":"286","author":"Ong","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S101","DOI":"10.1017\/S0031182097001133","article-title":"New approaches to Leishmania chemotherapy: Pteridine Reductase 1 (PTR1) as a target and modulator of antifolate sensitivity","volume":"114","author":"Nare","year":"1997","journal-title":"Parasitology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1080\/17460441.2022.2113776","article-title":"Anti-trypanosomatid structure-based drug design\u2014Lessons learned from targeting the folate pathway","volume":"17","author":"Poehner","year":"2022","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_16","first-page":"65","article-title":"Inhibition of Leishmania major PTR1 Gene Expression by Antisense in Escherichia coli","volume":"41","author":"Kheirandish","year":"2012","journal-title":"Iran. J. Public Health"},{"key":"ref_17","first-page":"207","article-title":"Targeting pteridine reductase 1 and dihydrofolate reductase: The old is a new trend for leishmaniasis drug discovery","volume":"11","author":"Kagami","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Possart, K., Herrmann, F.C., Jose, J., Costi, M.P., and Schmidt, T.J. (2022). Sesquiterpene Lactones with Dual Inhibitory Activity against the Trypanosoma brucei Pteridine Reductase 1 and Dihydrofolate Reductase. Molecules, 27.","DOI":"10.3390\/molecules27010149"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1080\/14756366.2019.1651311","article-title":"Dual and selective inhibitors of pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS) from Leishmania chagasi","volume":"34","author":"Teixeira","year":"2019","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"114959","DOI":"10.1016\/j.ejmech.2022.114959","article-title":"New antileishmanial quinoline linked isatin derivatives targeting DHFR-TS and PTR1: Design, synthesis, and molecular modeling studies","volume":"246","author":"Sabt","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Nogueira, M.S., Da Costa, F.B., Brun, R., Kaiser, M., and Schmidt, T.J. (2016). Ent-pimarane and ent-kaurane diterpenes from Aldama discolor (Asteraceae) and their antiprotozoal activity. Molecules, 21.","DOI":"10.3390\/molecules21091237"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"392918","DOI":"10.1155\/2015\/392918","article-title":"Kaurenoic acid possesses leishmanicidal activity by triggering a NLRP12\/IL-1 \u03b2\/cNOS\/NO Pathway","volume":"2015","author":"Miranda","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1590\/S0074-02762013000100010","article-title":"Antileishmanial activity of diterpene acids in copaiba oil","volume":"108","author":"Izumi","year":"2013","journal-title":"Mem. Inst. Oswaldo Cruz"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Herrera-Acevedo, C., Flores-Gaspar, A., Scotti, L., Mendon\u00e7a-Junior, F.J.B., Scotti, M.T., and Coy-Barrera, E. (2021). Identification of Kaurane-type diterpenes as inhibitors of Leishmania pteridine reductase I. Molecules, 26.","DOI":"10.3390\/molecules26113076"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/0006-2952(73)90196-2","article-title":"the concentration of inhibitor which causes 50 percent inhibition (I) of an enzymatic reaction","volume":"22","author":"Cheng","year":"1973","journal-title":"Biochem. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e2200133","DOI":"10.1002\/minf.202200133","article-title":"MolPredictX: Online Biological Activity Predictions by Machine Learning Models","volume":"41","author":"Scotti","year":"2022","journal-title":"Mol. Inform."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1002\/prot.10286","article-title":"Structure validation by C\u03b1 geometry: \u03d5, \u03c8, and C\u03b2 deviation","volume":"50","author":"Lovell","year":"2003","journal-title":"Proteins"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1107\/S0021889892008240","article-title":"Quality control of protein models: Directional atomic contact analysis","volume":"26","author":"Vriend","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.2169\/internalmedicine.4096-19","article-title":"Failure of liposomal-amphotericin B treatment for new world cutaneous leishmaniasis due to leishmania braziliensis","volume":"59","author":"Kosaka","year":"2020","journal-title":"Intern. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/s41597-020-0451-5","article-title":"An interactive database of Leishmania species distribution in the Americas","volume":"7","author":"Herrera","year":"2020","journal-title":"Sci. Data"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e200572","DOI":"10.1590\/0074-02760200572","article-title":"Evaluation of cytochrome b sequence to identify Leishmania species and variants: The case of Panama","volume":"116","author":"Davila","year":"2021","journal-title":"Mem\u00f3rias Do Inst. Oswaldo Cruz"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111688","DOI":"10.1016\/j.ejmech.2019.111688","article-title":"Synthesis of cinnamic acid derivatives and leishmanicidal activity against Leishmania braziliensis","volume":"183","author":"Rodrigues","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108244","DOI":"10.1016\/j.exppara.2022.108244","article-title":"In vitro activity of cinnamaldehyde on Leishmania (Leishmania) amazonensis","volume":"236","author":"Brustolin","year":"2022","journal-title":"Exp. Parasitol."},{"key":"ref_34","unstructured":"Feigin, R.D., Cherry, J.D., Demmler-Harrison, G.J., and Kaplan, S.L. (2009). Feigin and Cherry\u2019s Textbook of Pediatric Infectious Diseases, W.B. Saunders. [6th ed.]."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1021\/acs.jnatprod.8b00189","article-title":"Tetrahydrobenzofuran-6 (2 H)-one neolignans from Ocotea heterochroma: Their platelet activating factor (PAF) antagonistic activity and in silico insights into the PAF receptor binding mode","volume":"81","author":"Schmidt","year":"2018","journal-title":"J. Nat. Prod."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3776","DOI":"10.1021\/bi00410a039","article-title":"V Heterologous Expression of the Bifunctional Thymidylate Synthase-Dihydrofolate Reductase from Leishmania major","volume":"27","author":"Grumont","year":"1988","journal-title":"Biochemistry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"13883","DOI":"10.1074\/jbc.272.21.13883","article-title":"The roles of pteridine reductase 1 and dihydrofolate reductase- thymidylate synthase in pteridine metabolism in the protozoan parasite Leishmania major","volume":"272","author":"Nare","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2413","DOI":"10.1016\/0031-9422(91)83666-9","article-title":"Tetracyclic diterpenols from Euphorbia sieboldiana","volume":"30","year":"1991","journal-title":"Phytochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7807","DOI":"10.1016\/j.tet.2010.07.059","article-title":"A chemoenzymatic total synthesis of the hirsutene-type sesquiterpene (+)-connatusin B from toluene","volume":"66","author":"Bon","year":"2010","journal-title":"Tetrahedron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1093\/bioinformatics\/btu426","article-title":"YASARA View\u2014Molecular graphics for all devices\u2014From smartphones to workstations","volume":"30","author":"Krieger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","article-title":"PROCHECK: A program to check the stereochemical quality of protein structures","volume":"26","author":"Laskowski","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1002\/cmdc.201700743","article-title":"In silico studies designed to select sesquiterpene lactones with potential antichagasic activity from an in-house asteraceae database","volume":"13","author":"Acevedo","year":"2018","journal-title":"ChemMedChem"},{"key":"ref_43","first-page":"2411","article-title":"Selection of antileishmanial sesquiterpene lactones from SistematX database using a combined ligand-\/structure-based virtual screening approach","volume":"25","author":"Maia","year":"2020","journal-title":"Mol. Divers."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0010-4655(95)00042-E","article-title":"GROMACS: A message-passing parallel molecular dynamics implementation","volume":"91","author":"Berendsen","year":"1995","journal-title":"Comput. Phys. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/minf.201100135","article-title":"Free Energy Calculations by the Molecular Mechanics Poisson\u2212 Boltzmann Surface Area Method","volume":"31","author":"Homeyer","year":"2012","journal-title":"Mol. Inform."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1021\/ci500020m","article-title":"g_mmpbsa\u2014A GROMACS Tool for High-Throughput MM-PBSA Calculations","volume":"54","author":"Kumari","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10037","DOI":"10.1073\/pnas.181342398","article-title":"Electrostatics of Nanosystems: Application to Microtubules and the Ribosome","volume":"98","author":"Baker","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Antibiotics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/4\/663\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:04:55Z","timestamp":1760123095000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6382\/12\/4\/663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,28]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["antibiotics12040663"],"URL":"https:\/\/doi.org\/10.3390\/antibiotics12040663","relation":{},"ISSN":["2079-6382"],"issn-type":[{"value":"2079-6382","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,28]]}}}