Ibuprofen reverts antifungal resistance onCandida albicansshowing overexpression of CDR genes

Abstract

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.

Ibuprofen Potentiates the In Vivo Antifungal Activity of Fluconazole against Candida albicans Murine Infection

“…Previously, we showed that the antifungal resistance conferred by increased efflux activity, due to overexpression of the CDR1 and CDR2 genes, in Candida clinical strains can be reversed by ibuprofen (9,10). This effect is also observed with other drugs, such as pyrazinamide (11) and amphotericin B (12).…”

The Monoamine Oxidase A Inhibitor Clorgyline Is a Broad-Spectrum Inhibitor of Fungal ABC and MFS Transporter Efflux Pump Activities Which Reverses the Azole Resistance of Candida albicans and Candida glabrata Clinical Isolates

“…Screening for chemosensitization in agar diffusion assays or liquid growth assays has been used to identify inhibitors of fungal efflux pumps. The application of these usually non-high-throughput screens, to panels of xenobiotics (23), combinatorial peptide libraries (33), and libraries of natural products (46) has identified tacrolimus (FK506), milbemycins (23), enniatins, beauvericin, unnarmicins (46), ibuprofen (40), tetandrine (52), cerulenin analogs (9), and some octapeptides (33) as specific fungal ABC pump inhibitors. Ideally, such compounds will inhibit a range of clinically important efflux pumps but not human orthologs.…”

In Vitro Antimycotic Evaluation and Preliminary Combinatorial Studies of Ibuprofen With Standard Antifungal Drugs Against Aspergillus Spp.

“…In addition, the IBU has also been reported to induce blocking of the efflux pumps such that reverting resistant Candida spp. into susceptible ones, against azoles [9,10].…”