Chemoproteomic identification of molecular targets of antifungal prototypes, thiosemicarbazide and a camphene derivative of thiosemicarbazide, in Paracoccidioides brasiliensis
Paracoccidioidomycosis (PCM) is a neglected human systemic disease caused by species of the genus Paracoccidioides. The disease attacks the host's lungs and may disseminate to many other organs. Treatment involves amphotericin B, sulfadiazine, trimethoprim-sulfamethoxazole, itraconazole, ketoco...
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| creator | Borba, Joyce Villa Verde Bastos Tauhata, Sinji Borges Ferreira Oliveira, Cecília Maria Alves de Ferreira Marques, Monique Bailão, Alexandre Melo Soares, Célia Maria de Almeida Pereira, Maristela |
| description | Paracoccidioidomycosis (PCM) is a neglected human systemic disease caused by species of the genus Paracoccidioides. The disease attacks the host's lungs and may disseminate to many other organs. Treatment involves amphotericin B, sulfadiazine, trimethoprim-sulfamethoxazole, itraconazole, ketoconazole, or fluconazole. The treatment duration is usually long, from 6 months to 2 years, and many adverse effects may occur in relation to the treatment; co-morbidities and poor treatment adherence have been noted. Therefore, the discovery of more effective and less toxic drugs is needed. Thiosemicarbazide (TSC) and a camphene derivative of thiosemicarbazide (TSC-C) were able to inhibit P. brasiliensis growth at a low dosage and were not toxic to fibroblast cells. In order to investigate the mode of action of those compounds, we used a chemoproteomic approach to determine which fungal proteins were bound to each of these compounds. The compounds were able to inhibit the activities of the enzyme formamidase and interfered in P. brasiliensis dimorphism. In comparison with the transcriptomic and proteomic data previously obtained by our group, we determined that TSC and TSC-C were multitarget compounds that exerted effects on the electron-transport chain and cell cycle regulation, increased ROS formation, inhibited proteasomes and peptidases, modulated glycolysis, lipid, protein and carbohydrate metabolisms, and caused suppressed the mycelium to yeast transition. |
| doi_str_mv | 10.1371/journal.pone.0201948 |
| format | Article |
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The disease attacks the host's lungs and may disseminate to many other organs. Treatment involves amphotericin B, sulfadiazine, trimethoprim-sulfamethoxazole, itraconazole, ketoconazole, or fluconazole. The treatment duration is usually long, from 6 months to 2 years, and many adverse effects may occur in relation to the treatment; co-morbidities and poor treatment adherence have been noted. Therefore, the discovery of more effective and less toxic drugs is needed. Thiosemicarbazide (TSC) and a camphene derivative of thiosemicarbazide (TSC-C) were able to inhibit P. brasiliensis growth at a low dosage and were not toxic to fibroblast cells. In order to investigate the mode of action of those compounds, we used a chemoproteomic approach to determine which fungal proteins were bound to each of these compounds. The compounds were able to inhibit the activities of the enzyme formamidase and interfered in P. brasiliensis dimorphism. In comparison with the transcriptomic and proteomic data previously obtained by our group, we determined that TSC and TSC-C were multitarget compounds that exerted effects on the electron-transport chain and cell cycle regulation, increased ROS formation, inhibited proteasomes and peptidases, modulated glycolysis, lipid, protein and carbohydrate metabolisms, and caused suppressed the mycelium to yeast transition.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0201948</identifier><identifier>PMID: 30148835</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amidohydrolases - metabolism ; Amphotericin B ; Animals ; Antifungal agents ; Antifungal Agents - chemistry ; Antifungal Agents - isolation & purification ; Antifungal Agents - pharmacology ; Apoptosis ; BALB 3T3 Cells ; Biology and Life Sciences ; Camphene ; Carbohydrates ; Cell cycle ; Cell division ; Cell Survival - drug effects ; Chemical properties ; Dimorphism ; Drug Discovery ; Drug therapy ; Enzyme Activation - drug effects ; Fluconazole ; Formamidase ; Fungal infections ; Fungal Proteins - antagonists & inhibitors ; Fungal Proteins - metabolism ; Fungi ; Fungicides ; Glycolysis ; Humans ; Identification and classification ; Itraconazole ; Ketoconazole ; Lungs ; Mice ; Microbial Sensitivity Tests ; Mode of action ; Morphogenesis ; Organs ; Paracoccidioides - drug effects ; Paracoccidioides - metabolism ; Paracoccidioidomycosis ; Peptidases ; Phylogenetics ; Proteasomes ; Protein Binding ; Proteins ; Proteomics ; Proteomics - methods ; Prototypes ; Semicarbazides - chemistry ; Semicarbazides - isolation & purification ; Semicarbazides - pharmacology ; South American blastomycosis ; Sulfadiazine ; Sulfamethoxazole ; Target recognition ; Thiosemicarbazides ; Trimethoprim ; Trimethoprim-sulfamethoxazole ; Yeast ; Yeasts</subject><ispartof>PloS one, 2018-08, Vol.13 (8), p.e0201948</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Borba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2018 Borba et al 2018 Borba et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-307e1eb557c5567d1123cb1ee24c25bd9b0387d6d47e72e58441c85b7e385be23</citedby><cites>FETCH-LOGICAL-c692t-307e1eb557c5567d1123cb1ee24c25bd9b0387d6d47e72e58441c85b7e385be23</cites><orcidid>0000-0002-5482-8036</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110461/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110461/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30148835$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Borba, Joyce Villa Verde Bastos</creatorcontrib><creatorcontrib>Tauhata, Sinji Borges Ferreira</creatorcontrib><creatorcontrib>Oliveira, Cecília Maria Alves de</creatorcontrib><creatorcontrib>Ferreira Marques, Monique</creatorcontrib><creatorcontrib>Bailão, Alexandre Melo</creatorcontrib><creatorcontrib>Soares, Célia Maria de Almeida</creatorcontrib><creatorcontrib>Pereira, Maristela</creatorcontrib><title>Chemoproteomic identification of molecular targets of antifungal prototypes, thiosemicarbazide and a camphene derivative of thiosemicarbazide, in Paracoccidioides brasiliensis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Paracoccidioidomycosis (PCM) is a neglected human systemic disease caused by species of the genus Paracoccidioides. The disease attacks the host's lungs and may disseminate to many other organs. Treatment involves amphotericin B, sulfadiazine, trimethoprim-sulfamethoxazole, itraconazole, ketoconazole, or fluconazole. The treatment duration is usually long, from 6 months to 2 years, and many adverse effects may occur in relation to the treatment; co-morbidities and poor treatment adherence have been noted. Therefore, the discovery of more effective and less toxic drugs is needed. Thiosemicarbazide (TSC) and a camphene derivative of thiosemicarbazide (TSC-C) were able to inhibit P. brasiliensis growth at a low dosage and were not toxic to fibroblast cells. In order to investigate the mode of action of those compounds, we used a chemoproteomic approach to determine which fungal proteins were bound to each of these compounds. The compounds were able to inhibit the activities of the enzyme formamidase and interfered in P. brasiliensis dimorphism. 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drug effects</subject><subject>Fluconazole</subject><subject>Formamidase</subject><subject>Fungal infections</subject><subject>Fungal Proteins - antagonists & inhibitors</subject><subject>Fungal Proteins - metabolism</subject><subject>Fungi</subject><subject>Fungicides</subject><subject>Glycolysis</subject><subject>Humans</subject><subject>Identification and classification</subject><subject>Itraconazole</subject><subject>Ketoconazole</subject><subject>Lungs</subject><subject>Mice</subject><subject>Microbial Sensitivity Tests</subject><subject>Mode of action</subject><subject>Morphogenesis</subject><subject>Organs</subject><subject>Paracoccidioides - drug effects</subject><subject>Paracoccidioides - metabolism</subject><subject>Paracoccidioidomycosis</subject><subject>Peptidases</subject><subject>Phylogenetics</subject><subject>Proteasomes</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>Proteomics - methods</subject><subject>Prototypes</subject><subject>Semicarbazides - 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The disease attacks the host's lungs and may disseminate to many other organs. Treatment involves amphotericin B, sulfadiazine, trimethoprim-sulfamethoxazole, itraconazole, ketoconazole, or fluconazole. The treatment duration is usually long, from 6 months to 2 years, and many adverse effects may occur in relation to the treatment; co-morbidities and poor treatment adherence have been noted. Therefore, the discovery of more effective and less toxic drugs is needed. Thiosemicarbazide (TSC) and a camphene derivative of thiosemicarbazide (TSC-C) were able to inhibit P. brasiliensis growth at a low dosage and were not toxic to fibroblast cells. In order to investigate the mode of action of those compounds, we used a chemoproteomic approach to determine which fungal proteins were bound to each of these compounds. The compounds were able to inhibit the activities of the enzyme formamidase and interfered in P. brasiliensis dimorphism. In comparison with the transcriptomic and proteomic data previously obtained by our group, we determined that TSC and TSC-C were multitarget compounds that exerted effects on the electron-transport chain and cell cycle regulation, increased ROS formation, inhibited proteasomes and peptidases, modulated glycolysis, lipid, protein and carbohydrate metabolisms, and caused suppressed the mycelium to yeast transition.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>30148835</pmid><doi>10.1371/journal.pone.0201948</doi><tpages>e0201948</tpages><orcidid>https://orcid.org/0000-0002-5482-8036</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2018-08, Vol.13 (8), p.e0201948 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2094365993 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Amidohydrolases - metabolism Amphotericin B Animals Antifungal agents Antifungal Agents - chemistry Antifungal Agents - isolation & purification Antifungal Agents - pharmacology Apoptosis BALB 3T3 Cells Biology and Life Sciences Camphene Carbohydrates Cell cycle Cell division Cell Survival - drug effects Chemical properties Dimorphism Drug Discovery Drug therapy Enzyme Activation - drug effects Fluconazole Formamidase Fungal infections Fungal Proteins - antagonists & inhibitors Fungal Proteins - metabolism Fungi Fungicides Glycolysis Humans Identification and classification Itraconazole Ketoconazole Lungs Mice Microbial Sensitivity Tests Mode of action Morphogenesis Organs Paracoccidioides - drug effects Paracoccidioides - metabolism Paracoccidioidomycosis Peptidases Phylogenetics Proteasomes Protein Binding Proteins Proteomics Proteomics - methods Prototypes Semicarbazides - chemistry Semicarbazides - isolation & purification Semicarbazides - pharmacology South American blastomycosis Sulfadiazine Sulfamethoxazole Target recognition Thiosemicarbazides Trimethoprim Trimethoprim-sulfamethoxazole Yeast Yeasts |
| title | Chemoproteomic identification of molecular targets of antifungal prototypes, thiosemicarbazide and a camphene derivative of thiosemicarbazide, in Paracoccidioides brasiliensis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T04%3A37%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Chemoproteomic%20identification%20of%20molecular%20targets%20of%20antifungal%20prototypes,%20thiosemicarbazide%20and%20a%20camphene%20derivative%20of%20thiosemicarbazide,%20in%20Paracoccidioides%20brasiliensis&rft.jtitle=PloS%20one&rft.au=Borba,%20Joyce%20Villa%20Verde%20Bastos&rft.date=2018-08-27&rft.volume=13&rft.issue=8&rft.spage=e0201948&rft.pages=e0201948-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0201948&rft_dat=%3Cgale_plos_%3EA551929567%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2094365993&rft_id=info:pmid/30148835&rft_galeid=A551929567&rft_doaj_id=oai_doaj_org_article_1f646fc79310423a9a7eff3efff2fa8b&rfr_iscdi=true |