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"idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Caso clínico</span>" "titulo" => "Problemas clínicos en micología médica: problema número 54" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "107" "paginaFinal" => "109" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Clinical problems in Medical Mycology: problem number 54" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 476 "Ancho" => 750 "Tamanyo" => 104016 ] ] "descripcion" => array:1 [ "es" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Examen microscópico al estado fresco del material 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array:2 [ "nombre" => "Juan Antonio" "apellidos" => "Gallegos-Marín" ] 5 => array:2 [ "nombre" => "Denisse Sinaí" "apellidos" => "Jiménez-Hernández" ] ] ] ] ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1130140620300346?idApp=UINPBA00004N" "url" => "/11301406/0000003700000034/v2_202012290734/S1130140620300346/v2_202012290734/es/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Note</span>" "titulo" => "Synergistic interactions between β-lapachone and fluconazole in the inhibition of CaCdr2p and CaMdr1p in <span class="elsevierStyleItalic">Candida albicans</span>" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "104" "paginaFinal" => "106" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Daniel Clemente Moraes, Leandro Figueira Reis de Sá, Levy Tenorio Sousa Domingos, Maria do Carmo Freire Ribeiro Pinto, Rosangela Maria de Araújo Soares, Antônio Ferreira-Pereira" "autores" => array:6 [ 0 => array:3 [ "nombre" => "Daniel Clemente" "apellidos" => "Moraes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "Leandro Figueira" "apellidos" => "Reis de Sá" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Levy Tenorio Sousa" "apellidos" => "Domingos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Maria do Carmo Freire Ribeiro" "apellidos" => "Pinto" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "Rosangela Maria de Araújo" "apellidos" => "Soares" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:4 [ "nombre" => "Antônio" "apellidos" => "Ferreira-Pereira" "email" => array:1 [ 0 => "apereira@micro.ufrj.br" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Laboratório de Bioquímica Microbiana, Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Goés, Universidade Federal do Rio de Janeiro, Brazil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Brazil" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Las interacciones sinérgicas entre la β-lapachona y el fluconazol en la inhibición de CaCdr2p y CaMdr1p en <span class="elsevierStyleItalic">Candida albicans</span>" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Candida</span> species are the major fungal pathogens that threaten human beings, especially those under immunosuppressive conditions, leading to potentially fatal infections.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Fluconazole is the first-choice substance to treat <span class="elsevierStyleItalic">Candida</span> infections. However, the overuse of azole drugs during the last decades have induced the appearance of resistant strains. Furthermore, there are few antifungal agents available to treat candidiasis. These circumstances point to an urgent need of discovering new therapeutic strategies to overcome <span class="elsevierStyleItalic">Candida</span> infections.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The development of antifungal resistance is related to the multidrug resistance (MDR) phenotype, which consists in cross resistance between structurally unrelated substances. Concerning <span class="elsevierStyleItalic">Candida</span>, its pivotal mechanism relies on the overexpression of ATP-binding cassette (ABC) and major facilitator superfamily (MFS) transporters within plasma membrane.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12,13</span></a> Impairing the activity of these proteins would allow fluconazole to reach the intracellular concentrations required to exert its antifungal activity.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In a previous study,<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> we observed that β-lapachone, a natural naphthoquinone that displays several pharmacological activities, inhibits <span class="elsevierStyleItalic">Saccharomyces cerevisiae</span> MDR protein Pdr5p, which is homologous to <span class="elsevierStyleItalic">Candida albicans</span> efflux transporters. Therefore, the aim of the present study was to assess whether β-lapachone may inhibit efflux proteins related to MDR in <span class="elsevierStyleItalic">C. albicans</span>.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Material and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">Four mutant strains of <span class="elsevierStyleItalic">S. cerevisiae</span> were used; AD/1234567 was deleted from all genes related to MDR transporters, while CaCdr1p+, CaCdr2p+ and CaMdr1p+ strains were derived from AD/1234567 but heterologously overexpress CaCdr1p, CaCdr2p and CaMdr1p, transporters naturally found in <span class="elsevierStyleItalic">C. albicans</span>.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Moreover, three <span class="elsevierStyleItalic">C. albicans</span> strains were used. Strain 95-142 overexpresses both CaCdr1p and CaCdr2p,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> while PRI overexpresses CaMdr1p.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> ATCC 10231™ strain does not overexpress MDR transporters and was used as control. The <span class="elsevierStyleItalic">S. cerevisiae</span> strains were kindly gifted by Drs. Richard Cannon and Brian Monk (University of Otago), and the strain 95-142 by Theodore White (University of Missouri). PRI strain is part of our yeast collection, and was collected from a subgingival secretion of an HIV-patient.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> CaCdr2p+ strains plasma membranes were obtained and stored at liquid nitrogen.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Before each procedure, cells were incubated in yeast-peptone-dextrose medium (YPD) during 17<span class="elsevierStyleHsp" style=""></span>h at 30<span class="elsevierStyleHsp" style=""></span>°C (<span class="elsevierStyleItalic">S. cerevisiae</span>) or 37<span class="elsevierStyleHsp" style=""></span>°C (<span class="elsevierStyleItalic">C. albicans</span>) at 100<span class="elsevierStyleHsp" style=""></span>rpm. β-lapachone was synthesized from lapachol.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Agarose, RPMI-1640, rhodamine 6G (R6G), and Nile red were purchased from Sigma Aldrich (St. Louis, USA), and fluconazole was purchased from Farmacopa (Rio de Janeiro, Brazil). Antifungal activity of β-lapachone, alone or combined with fluconazole, was firstly evaluated in <span class="elsevierStyleItalic">S. cerevisiae</span> mutant strains through the agarose diffusion chemosensitization assay.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Cell suspensions were incorporated into molten YPD agar medium in the presence or absence of fluconazole. Then, 50<span class="elsevierStyleHsp" style=""></span>μg of β-lapachone were applied onto 6-milimeter Whatman 3MM® paper disks (Sigma–Aldrich®) and placed on the surface of the plate. Plates were incubated at 30<span class="elsevierStyleHsp" style=""></span>°C for 48<span class="elsevierStyleHsp" style=""></span>h. A microdilution method was performed in order to evaluate the minimal inhibitory concentration (MIC) of β-lapachone and to assess the interaction between this substance and fluconazole.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Four strains, namely CaCdr2p+, CaMdr1p+, 95-142, and PRI were used in this procedure.</p><p id="par0030" class="elsevierStylePara elsevierViewall">To verify if β-lapachone and fluconazole have a synergic activity due to efflux transporters inhibition, an assay with fluorescent probes was carried on. Efflux assays were performed using the R6G and Nile red fluorescent probes to evaluate the inhibition of CaCdr2p<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and CaMdr1p,<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> respectively. AD/1234567 and ATCC 10231 were used as control. CaCdr2p is an ABC transporter and then it hydrolyses ATP to promote the efflux of substances. Blocking its ATPase activity could hamper efflux process and sensitize the yeasts to fluconazole. CaCdr2p ATPase activity was measured through incubation of enriched-plasma membranes in presence or absence of β-lapachone at 100<span class="elsevierStyleHsp" style=""></span>μg/ml.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Results</span><p id="par0035" class="elsevierStylePara elsevierViewall">In agarose diffusion chemosensitization assay, halo diameters larger than 6<span class="elsevierStyleHsp" style=""></span>mm were considered as growth inhibition. In absence of fluconazole, β-lapachone inhibited the growth of CaCdr2p+ (11 mm-diameter) and CaMdr1p+ (11<span class="elsevierStyleHsp" style=""></span>mm-diameter) strains. Furthermore, it was observed that β-lapachone improved the antifungal activity of fluconazole against the same strains (15<span class="elsevierStyleHsp" style=""></span>mm-diameter). Since these microorganisms overexpress CaCdr2p or CaMdr1p, fluconazole resistant <span class="elsevierStyleItalic">C. albicans</span> strains, namely 95-142 and PRI, that possess the same efflux proteins, were used in the following experiments.</p><p id="par0040" class="elsevierStylePara elsevierViewall">MIC of β-lapachone was assessed since it showed antifungal activity in the previous experiment. β-lapachone impaired the growth of <span class="elsevierStyleItalic">S. cerevisiae</span> strains and <span class="elsevierStyleItalic">C. albicans</span> isolates, with MIC values of 25<span class="elsevierStyleHsp" style=""></span>μg/ml for CaCdr2p+ strain, 12.5<span class="elsevierStyleHsp" style=""></span>μg/ml for CaMdr1p+ strain, and 100<span class="elsevierStyleHsp" style=""></span>μg/ml for both <span class="elsevierStyleItalic">C. albicans</span> strains. Combinations were evaluated using fractional inhibition concentration index (FICI). FICI<span class="elsevierStyleHsp" style=""></span>≤<span class="elsevierStyleHsp" style=""></span>0.5 points to a synergic interaction, whereas 0.5<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>FICI<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>4.0 indicates synergism, and FICI<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>4 indicates antagonistic interaction.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The FICI calculated for all the tested strains were less than or equal to 0.5, implying that the combination of β-lapachone and fluconazole was synergic (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The data obtained show that β-lapachone impaired the efflux mechanism in CaCdr2p+, CaMdr1p+, 95-142 and PRI strains at 74.9%, 49%, 28.1% and 43%, respectively. Neither AD/1234567 nor ATCC 10231 were able to extrude the probes, being used as negative controls. Results show that β-lapachone does not inhibit efflux through decreasing CaCdr2p ATPase activity.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0045" class="elsevierStylePara elsevierViewall">Our results show that β-lapachone inhibit CaCdr2p and CaMdr1p, two of the three main transporters involved in MDR phenotype within <span class="elsevierStyleItalic">C. albicans</span>, thereby allowing fluconazole to reach intracellular concentrations required to its antifungal activity. Interestingly, despite the homology between CaCdr1p and CaCdr2p, only the latter was inhibited by β-lapachone. Moreover, β-lapachone did not inhibit CaCdr2p ATPase activity; it was unexpected, considering the results obtained on our previous study, where β-lapachone inhibited Pdr5p ATPase activity.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> This data shows that, although CaCdr2p and Pdr5p are homologous proteins, substances may act differently at each transporter. Therefore, our results corroborate that the ability of inhibiting ABC efflux transporters is not mandatorily related to ATPase activity impairment.</p><p id="par0050" class="elsevierStylePara elsevierViewall">In summary, it can be concluded that β-lapachone is a promising drug candidate to be used as an adjuvant in the treatment of candidiasis caused by fluconazole-resistant strains. Further in vivo studies need to be conducted to clarify the applicability of this combination on infections caused by <span class="elsevierStyleItalic">Candida</span>.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Funding sources</span><p id="par0060" class="elsevierStylePara elsevierViewall">This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (<span class="elsevierStyleGrantSponsor" id="gs1">CAPES</span>) – Finance Code 001.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conflict of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">None.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1442121" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1316158" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1442122" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1316159" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Material and methods" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Results" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding sources" ] 8 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflict of interest" ] 9 => array:2 [ "identificador" => "xack503360" "titulo" => "Acknowledgments" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2020-06-22" "fechaAceptado" => "2020-09-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1316158" "palabras" => array:6 [ 0 => "<span class="elsevierStyleItalic">Candida albicans</span>" 1 => "Fluconazole resistance" 2 => "ABC transporters" 3 => "MFS transporters" 4 => "β-lapachone" 5 => "Yeast" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1316159" "palabras" => array:6 [ 0 => "<span class="elsevierStyleItalic">Candida albicans</span>" 1 => "Resistencia al fluconazol" 2 => "Transportadores ABC" 3 => "Transportadores MFS" 4 => "β-lapachona" 5 => "Levadura" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mortality rate of invasive <span class="elsevierStyleItalic">Candida</span> infections is raising mainly amongst immunocompromised patients. These infections are hard-to-treat mainly due to the increasing incidence of resistance. The overexpression of ATP-binding cassette and major facilitator superfamily transporters is the main responsible for the failure of antifungal therapies. In a <span class="elsevierStyleItalic">Saccharomyces cerevisiae</span> model, β-lapachone inhibited Pdr5p, a transporter homologous to those found in <span class="elsevierStyleItalic">Candida albicans</span>.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Aims</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To determine whether β-lapachone reverses the resistance phenotype mediated by efflux transporters in <span class="elsevierStyleItalic">C</span>. <span class="elsevierStyleItalic">albicans</span> clinical isolates.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The antifungal activity of β-lapachone combined with fluconazole was measured by agarose chemosensitization and microdilution assays. CaCdr2p and CaMdr1p activities were evaluated through fluorescent dyes accumulation. ATPase activity was assessed using transporter-enriched plasma membranes.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">β-lapachone reverted antifungal resistance of <span class="elsevierStyleItalic">S. cerevisiae</span> and <span class="elsevierStyleItalic">C. albicans</span> strains overexpressing CaCdr2p and CaMdr1p transporters by inhibiting these proteins activities. CaCdr2p ATPase activity was not impaired by the compound.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">β-lapachone is a promising drug candidate to be used as an adjuvant in the treatment of candidiasis caused by fluconazole-resistant <span class="elsevierStyleItalic">C. albicans</span> strains.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Las tasas de mortalidad de infecciones invasivas causadas por <span class="elsevierStyleItalic">Candida</span> están en aumento, principalmente entre los pacientes inmunocomprometidos. Estas infecciones son difíciles de tratar debido a la creciente incidencia de resistencia a los antifúngicos. La sobreexpresión de los transportadores dependientes de ATP y los de la superfamilia de facilitadores principales es el mayor responsable del fracaso de las terapias antimicóticas. En un modelo de <span class="elsevierStyleItalic">Saccharomyces cerevisiae</span>, la β-lapachona inhibió Pdr5p, un transportador homólogo a los encontrados en <span class="elsevierStyleItalic">Candida albicans</span>.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Determinar si la β-lapachona revierte el fenotipo de resistencia mediado por transportadores de eflujo en aislamientos clínicos de <span class="elsevierStyleItalic">C. albicans</span>.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Métodos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Se midió la actividad antifúngica de la β-lapachona combinada con fluconazol mediante ensayos de quimiosensibilización con agarosa y microdilución. Las actividades CaCdr2p y CaMdr1p se evaluaron mediante la acumulación de colorantes fluorescentes, y la actividad de ATPasa se evaluó usando membranas plasmáticas enriquecidas con transportador.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">La β-lapachona revirtió la resistencia antifúngica de las cepas de <span class="elsevierStyleItalic">S. cerevisiae</span> y <span class="elsevierStyleItalic">C. albicans</span> que sobreexpresaban los transportadores CaCdr2p y CaMdr1p al inhibir sus actividades. El compuesto no afectó la actividad ATPasa de CaCdr2p.</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">La β-lapachona es una candidata prometedora para ser utilizada como adyuvante en el tratamiento de la candidiasis causada por cepas de <span class="elsevierStyleItalic">C. albicans</span> resistentes al fluconazol.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">MIC: minimal inhibitory concentration; FIC: ratio between MIC of a compound combined with a second compound and its MIC alone; FICI: sum of each FIC value.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Species (strain) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">β-lapachone</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Fluconazole</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">FICI \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Outcome \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC alone (μg/ml) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC combined (μg/ml) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FIC \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC alone (μg/ml) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MIC combined (μg/ml) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">FIC \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">S. cerevisiae</span> (CaCdr2p+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">256 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.375 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Synergy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">S. cerevisiae</span> (CaMdr1p+) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">12.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.500 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Synergy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">C. albicans</span> (95-142) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.031 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">512 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.156 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Synergy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">C. albicans</span> (PRI) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">100 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.125 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.031 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">128 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.062 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.093 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Synergy \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2480406.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Checkerboard assay of <span class="elsevierStyleItalic">S. cerevisiae</span> and <span class="elsevierStyleItalic">C. albicans</span> strains overexpressing multidrug efflux pumps CaCDR2p and CaMDR1p.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Targeting efflux pumps to overcome antifungal drug resistance" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "T.S. 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