Ibuprofen reverts antifungal resistance on Candida albicans showing overexpression of CDR genes.
Several mechanisms may be associated with Candida albicans resistance to azoles. Ibuprofen was described as being able to revert resistance related to efflux activity in Candida. The aim of this study was to uncover the molecular base of antifungal resistance in C. albicans clinical strains that could be reverted by ibuprofen. Sixty-two clinical isolates and five control strains of C. albicans were studied: the azole susceptibility phenotype was determined according to the Clinical Laboratory for Standards Institute, M27-A2 protocol and minimal inhibitory concentration values were recalculated with ibuprofen (100 microg mL(-1)); synergistic studies between fluconazole and FK506, a Cdr1p inhibitor, were performed using an agar disk diffusion assay and were compared with ibuprofen results. Gene expression was quantified by real-time PCR, with and without ibuprofen, regarding CDR1, CDR2, MDR1, encoding for efflux pumps, and ERG11, encoding for azole target protein. A correlation between susceptibility phenotype and resistance gene expression profiles was determined. Ibuprofen and FK506 showed a clear synergistic effect when combined with fluconazole. Resistant isolates reverting to susceptible after incubation with ibuprofen showed CDR1 and CDR2 overexpression especially of the latter. Conversely, strains that did not revert displayed a remarkable increase in ERG11 expression along with CDR genes. Ibuprofen did not alter resistance gene expression significantly (P>0.05), probably acting as a Cdrp blocker.
Department of Microbiology, Faculty of Medicine, University of Porto, Porto, Portugal. betaricardo@yahoo.com
Elisabete
E
Ricardo
Sofia
S
Costa-de-Oliveira
Ana Silva
AS
Dias
José
J
Guerra
Acácio Gonçalves
AG
Rodrigues
Cidália
C
Pina-Vaz
D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000302:isolation & purification; D002177:Candidiasis / Q000382:microbiology; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000096:biosynthesis; D020869:Gene Expression Profiling; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D026901:Membrane Transport Proteins / Q000096:biosynthesis; D008826:Microbial Sensitivity Tests; D016559:Tacrolimus / Q000494:pharmacology
D000935:Antifungal Agents; D001393:Azoles; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D015725:Fluconazole; D007052:Ibuprofen; D016559:Tacrolimus