In vitro activity of the antifungal azoles itraconazole and posaconazole against Leishmania amazonensis
Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In r...
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| description | Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In resistant cases, miltefosine, amphotericin B and pentamidine are used. These treatments are unsatisfactory due to toxicity, limited efficacy, high cost and difficult administration. Thus, there is an urgent need to develop drugs that are efficacious, safe, and more accessible to patients. Trypanosomatids, including Leishmania spp. and Trypanosoma cruzi, have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. Inhibition of ergosterol biosynthesis is increasingly recognized as a promising target for the development of new chemotherapeutic agents. The aim of this work was to investigate the antiproliferative, physiological and ultrastructural effects against Leishmania amazonensis of itraconazole (ITZ) and posaconazole (POSA), two azole antifungal agents that inhibit sterol C14α-demethylase (CYP51). Antiproliferative studies demonstrated potent activity of POSA and ITZ: for promastigotes, the IC50 values were 2.74 µM and 0.44 µM for POSA and ITZ, respectively, and for intracellular amastigotes, the corresponding values were 1.63 µM and 0.08 µM, for both stages after 72 h of treatment. Physiological studies revealed that both inhibitors induced a collapse of the mitochondrial membrane potential (ΔΨm), which was consistent with ultrastructural alterations in the mitochondrion. Intense mitochondrial swelling, disorganization and rupture of mitochondrial membranes were observed by transmission electron microscopy. In addition, accumulation of lipid bodies, appearance of autophagosome-like structures and alterations in the kinetoplast were also observed. In conclusion, our results indicate that ITZ and POSA are potent inhibitors of L. amazonensis and suggest that these drugs could represent novel therapies for the treatment of leishmaniasis, either alone or in combination with other agents. |
| doi_str_mv | 10.1371/journal.pone.0083247 |
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F. H.</contributor><creatorcontrib>de Macedo-Silva, Sara Teixeira ; Urbina, Julio A ; de Souza, Wanderley ; Rodrigues, Juliany Cola Fernandes ; Schallig, Henk D. F. H.</creatorcontrib><description>Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In resistant cases, miltefosine, amphotericin B and pentamidine are used. These treatments are unsatisfactory due to toxicity, limited efficacy, high cost and difficult administration. Thus, there is an urgent need to develop drugs that are efficacious, safe, and more accessible to patients. Trypanosomatids, including Leishmania spp. and Trypanosoma cruzi, have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. Inhibition of ergosterol biosynthesis is increasingly recognized as a promising target for the development of new chemotherapeutic agents. The aim of this work was to investigate the antiproliferative, physiological and ultrastructural effects against Leishmania amazonensis of itraconazole (ITZ) and posaconazole (POSA), two azole antifungal agents that inhibit sterol C14α-demethylase (CYP51). Antiproliferative studies demonstrated potent activity of POSA and ITZ: for promastigotes, the IC50 values were 2.74 µM and 0.44 µM for POSA and ITZ, respectively, and for intracellular amastigotes, the corresponding values were 1.63 µM and 0.08 µM, for both stages after 72 h of treatment. Physiological studies revealed that both inhibitors induced a collapse of the mitochondrial membrane potential (ΔΨm), which was consistent with ultrastructural alterations in the mitochondrion. Intense mitochondrial swelling, disorganization and rupture of mitochondrial membranes were observed by transmission electron microscopy. In addition, accumulation of lipid bodies, appearance of autophagosome-like structures and alterations in the kinetoplast were also observed. In conclusion, our results indicate that ITZ and POSA are potent inhibitors of L. amazonensis and suggest that these drugs could represent novel therapies for the treatment of leishmaniasis, either alone or in combination with other agents.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0083247</identifier><identifier>PMID: 24376670</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alterations ; Amastigotes ; Amphotericin B ; Antifungal agents ; Antifungal Agents - pharmacology ; Antiprotozoal Agents - pharmacology ; Autophagy ; Azoles ; Biosynthesis ; Cells (Biology) ; Chemotherapy ; Cytochrome P-450 ; Drug Repositioning ; Drugs ; Electron microscopy ; Enzyme Inhibitors - pharmacology ; Ergosterol ; Fungicides ; Health aspects ; Heterocyclic compounds ; Inhibitors ; Inhibitory Concentration 50 ; Itraconazole ; Itraconazole - pharmacology ; Laboratory animals ; Leishmania ; Leishmania amazonensis ; Leishmania mexicana - drug effects ; Leishmania mexicana - enzymology ; Leishmania mexicana - ultrastructure ; Leishmaniasis ; Life Cycle Stages - drug effects ; Lipid bodies ; Mammalian cells ; Membrane potential ; Membrane Potential, Mitochondrial - drug effects ; Membranes ; Microscopy, Electron, Transmission ; Miltefosine ; Mitochondria ; Mitochondria - drug effects ; Mitochondria - enzymology ; Mitochondria - ultrastructure ; Morbidity ; Parasites ; Parasitic diseases ; Pentamidine ; Physiological aspects ; Physiological effects ; Physiology ; Phytosterols ; Plant lipids ; Posaconazole ; Promastigotes ; Protozoa ; Protozoan Proteins - antagonists & inhibitors ; Protozoan Proteins - metabolism ; Sterol 14-Demethylase - metabolism ; Sterols ; Target recognition ; Toxicity ; Transmission electron microscopy ; Triazoles - pharmacology ; Tropical diseases ; Trypanosoma cruzi ; Vector-borne diseases</subject><ispartof>PloS one, 2013-12, Vol.8 (12), p.e83247</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 de Macedo-Silva 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>2013 de Macedo-Silva et al 2013 de Macedo-Silva et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-c399809b9fe68289970f29b6a7b856c28c3d53f5d225a604661f40a180b5e8793</citedby><cites>FETCH-LOGICAL-c692t-c399809b9fe68289970f29b6a7b856c28c3d53f5d225a604661f40a180b5e8793</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871555/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871555/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24376670$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Schallig, Henk D. F. H.</contributor><creatorcontrib>de Macedo-Silva, Sara Teixeira</creatorcontrib><creatorcontrib>Urbina, Julio A</creatorcontrib><creatorcontrib>de Souza, Wanderley</creatorcontrib><creatorcontrib>Rodrigues, Juliany Cola Fernandes</creatorcontrib><title>In vitro activity of the antifungal azoles itraconazole and posaconazole against Leishmania amazonensis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In resistant cases, miltefosine, amphotericin B and pentamidine are used. These treatments are unsatisfactory due to toxicity, limited efficacy, high cost and difficult administration. Thus, there is an urgent need to develop drugs that are efficacious, safe, and more accessible to patients. Trypanosomatids, including Leishmania spp. and Trypanosoma cruzi, have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. Inhibition of ergosterol biosynthesis is increasingly recognized as a promising target for the development of new chemotherapeutic agents. The aim of this work was to investigate the antiproliferative, physiological and ultrastructural effects against Leishmania amazonensis of itraconazole (ITZ) and posaconazole (POSA), two azole antifungal agents that inhibit sterol C14α-demethylase (CYP51). Antiproliferative studies demonstrated potent activity of POSA and ITZ: for promastigotes, the IC50 values were 2.74 µM and 0.44 µM for POSA and ITZ, respectively, and for intracellular amastigotes, the corresponding values were 1.63 µM and 0.08 µM, for both stages after 72 h of treatment. Physiological studies revealed that both inhibitors induced a collapse of the mitochondrial membrane potential (ΔΨm), which was consistent with ultrastructural alterations in the mitochondrion. Intense mitochondrial swelling, disorganization and rupture of mitochondrial membranes were observed by transmission electron microscopy. In addition, accumulation of lipid bodies, appearance of autophagosome-like structures and alterations in the kinetoplast were also observed. In conclusion, our results indicate that ITZ and POSA are potent inhibitors of L. amazonensis and suggest that these drugs could represent novel therapies for the treatment of leishmaniasis, either alone or in combination with other agents.</description><subject>Alterations</subject><subject>Amastigotes</subject><subject>Amphotericin B</subject><subject>Antifungal agents</subject><subject>Antifungal Agents - pharmacology</subject><subject>Antiprotozoal Agents - pharmacology</subject><subject>Autophagy</subject><subject>Azoles</subject><subject>Biosynthesis</subject><subject>Cells (Biology)</subject><subject>Chemotherapy</subject><subject>Cytochrome P-450</subject><subject>Drug Repositioning</subject><subject>Drugs</subject><subject>Electron microscopy</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Ergosterol</subject><subject>Fungicides</subject><subject>Health aspects</subject><subject>Heterocyclic compounds</subject><subject>Inhibitors</subject><subject>Inhibitory Concentration 50</subject><subject>Itraconazole</subject><subject>Itraconazole - pharmacology</subject><subject>Laboratory animals</subject><subject>Leishmania</subject><subject>Leishmania amazonensis</subject><subject>Leishmania mexicana - drug effects</subject><subject>Leishmania mexicana - enzymology</subject><subject>Leishmania mexicana - ultrastructure</subject><subject>Leishmaniasis</subject><subject>Life Cycle Stages - drug effects</subject><subject>Lipid bodies</subject><subject>Mammalian cells</subject><subject>Membrane potential</subject><subject>Membrane Potential, Mitochondrial - drug effects</subject><subject>Membranes</subject><subject>Microscopy, Electron, Transmission</subject><subject>Miltefosine</subject><subject>Mitochondria</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - enzymology</subject><subject>Mitochondria - ultrastructure</subject><subject>Morbidity</subject><subject>Parasites</subject><subject>Parasitic diseases</subject><subject>Pentamidine</subject><subject>Physiological aspects</subject><subject>Physiological effects</subject><subject>Physiology</subject><subject>Phytosterols</subject><subject>Plant lipids</subject><subject>Posaconazole</subject><subject>Promastigotes</subject><subject>Protozoa</subject><subject>Protozoan Proteins - antagonists & inhibitors</subject><subject>Protozoan Proteins - metabolism</subject><subject>Sterol 14-Demethylase - metabolism</subject><subject>Sterols</subject><subject>Target recognition</subject><subject>Toxicity</subject><subject>Transmission electron microscopy</subject><subject>Triazoles - pharmacology</subject><subject>Tropical diseases</subject><subject>Trypanosoma cruzi</subject><subject>Vector-borne diseases</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkttq3DAQhk1padK0b1BaQ6HQi93qbOkmEEIPCwuBnm7FWJa9Cl5pa8mh6dNXm3XCGlooupA0880v8c8UxUuMlphW-P11GAcP_XIXvF0iJClh1aPiFCtKFoIg-vjofFI8i_EaIU6lEE-LE8JoJUSFTotu5csbl4ZQgkkun27L0JZpY0vwybWj76Av4XfobSwzBib4u1tON-UuxKNAB87HVK6ti5steAclbHPKWx9dfF48aaGP9sW0nxXfP374dvl5sb76tLq8WC-MUCQtDFVKIlWr1gpJpFIVaomqBVS15MIQaWjDacsbQjgIxITALUOAJaq5lZWiZ8Xrg-6uD1FPHkWNWYU4l0KKTKwORBPgWu8Gt4XhVgdw-i4Qhk7DkJzprVYGDOI1AcwYwwhLJiVjnOCaCkmVyVrn02tjvbWNsT5b1M9E5xnvNroLN5rKCnPOs8CbSWAIP0cb0z--PFG5GVY734Z9J7YuGn3BKonztzjK1PIvVF6N3brcJtu6HJ8VvJsVZCbZX6mDMUa9-vrl_9mrH3P27RG7sdCnTQz9mFzwcQ6yA2iGEONg2wfnMNL7Ib93Q--HXE9DnsteHbv-UHQ_1fQPGyP3BQ</recordid><startdate>20131223</startdate><enddate>20131223</enddate><creator>de Macedo-Silva, Sara Teixeira</creator><creator>Urbina, Julio A</creator><creator>de Souza, Wanderley</creator><creator>Rodrigues, Juliany Cola Fernandes</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131223</creationdate><title>In vitro activity of the antifungal azoles itraconazole and posaconazole against Leishmania amazonensis</title><author>de Macedo-Silva, Sara Teixeira ; Urbina, Julio A ; de Souza, Wanderley ; Rodrigues, Juliany Cola Fernandes</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-c399809b9fe68289970f29b6a7b856c28c3d53f5d225a604661f40a180b5e8793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Alterations</topic><topic>Amastigotes</topic><topic>Amphotericin B</topic><topic>Antifungal agents</topic><topic>Antifungal Agents - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>de Macedo-Silva, Sara Teixeira</au><au>Urbina, Julio A</au><au>de Souza, Wanderley</au><au>Rodrigues, Juliany Cola Fernandes</au><au>Schallig, Henk D. F. H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro activity of the antifungal azoles itraconazole and posaconazole against Leishmania amazonensis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-12-23</date><risdate>2013</risdate><volume>8</volume><issue>12</issue><spage>e83247</spage><pages>e83247-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In resistant cases, miltefosine, amphotericin B and pentamidine are used. These treatments are unsatisfactory due to toxicity, limited efficacy, high cost and difficult administration. Thus, there is an urgent need to develop drugs that are efficacious, safe, and more accessible to patients. Trypanosomatids, including Leishmania spp. and Trypanosoma cruzi, have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. Inhibition of ergosterol biosynthesis is increasingly recognized as a promising target for the development of new chemotherapeutic agents. The aim of this work was to investigate the antiproliferative, physiological and ultrastructural effects against Leishmania amazonensis of itraconazole (ITZ) and posaconazole (POSA), two azole antifungal agents that inhibit sterol C14α-demethylase (CYP51). Antiproliferative studies demonstrated potent activity of POSA and ITZ: for promastigotes, the IC50 values were 2.74 µM and 0.44 µM for POSA and ITZ, respectively, and for intracellular amastigotes, the corresponding values were 1.63 µM and 0.08 µM, for both stages after 72 h of treatment. Physiological studies revealed that both inhibitors induced a collapse of the mitochondrial membrane potential (ΔΨm), which was consistent with ultrastructural alterations in the mitochondrion. Intense mitochondrial swelling, disorganization and rupture of mitochondrial membranes were observed by transmission electron microscopy. In addition, accumulation of lipid bodies, appearance of autophagosome-like structures and alterations in the kinetoplast were also observed. In conclusion, our results indicate that ITZ and POSA are potent inhibitors of L. amazonensis and suggest that these drugs could represent novel therapies for the treatment of leishmaniasis, either alone or in combination with other agents.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24376670</pmid><doi>10.1371/journal.pone.0083247</doi><tpages>e83247</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-12, Vol.8 (12), p.e83247 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1470558686 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alterations Amastigotes Amphotericin B Antifungal agents Antifungal Agents - pharmacology Antiprotozoal Agents - pharmacology Autophagy Azoles Biosynthesis Cells (Biology) Chemotherapy Cytochrome P-450 Drug Repositioning Drugs Electron microscopy Enzyme Inhibitors - pharmacology Ergosterol Fungicides Health aspects Heterocyclic compounds Inhibitors Inhibitory Concentration 50 Itraconazole Itraconazole - pharmacology Laboratory animals Leishmania Leishmania amazonensis Leishmania mexicana - drug effects Leishmania mexicana - enzymology Leishmania mexicana - ultrastructure Leishmaniasis Life Cycle Stages - drug effects Lipid bodies Mammalian cells Membrane potential Membrane Potential, Mitochondrial - drug effects Membranes Microscopy, Electron, Transmission Miltefosine Mitochondria Mitochondria - drug effects Mitochondria - enzymology Mitochondria - ultrastructure Morbidity Parasites Parasitic diseases Pentamidine Physiological aspects Physiological effects Physiology Phytosterols Plant lipids Posaconazole Promastigotes Protozoa Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - metabolism Sterol 14-Demethylase - metabolism Sterols Target recognition Toxicity Transmission electron microscopy Triazoles - pharmacology Tropical diseases Trypanosoma cruzi Vector-borne diseases |
| title | In vitro activity of the antifungal azoles itraconazole and posaconazole against Leishmania amazonensis |
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