Resistance reversal induced by a combination of fluconazole and tacrolimus (FK506) in Candida glabrata

Abstract

There is an increasing concern about Candida glabrata due to its high isolation frequency in candidiasis recently and notorious drug resistance to fluconazole. Drug combination is one effective approach to counteract drug resistance. This study aimed to test whether a combination of fluconazole and tacrolimus (FK506) had a synergistic effect on C. glabrata, and to seek the potential mechanisms underlying the synergistic effects. In vitro effects of fluconazole and FK506 against C. glabrata with different susceptibilities were investigated by a chequerboard method and a time-kill curve method. The mechanistic studies against the resistant C. glabrata were performed from two aspects: quantification of expression levels of fluconazole resistance genes (ERG11, CDR1, PDH1 and SNQ2) by real-time quantitative PCR and functional assays of drug efflux pumps. The addition of FK506 resulted in a decrease in the MIC of fluconazole from 32 to 8 mg ml "1 against the dose-dependent susceptible C. glabrata, and from 256 to 16 mg ml "1 against the resistant C. glabrata, respectively. The synergy was further confirmed by the time-kill assay. The expression levels of the ERG11 and SNQ2 genes were significantly downregulated after exposure to the drug combination, whereas that of the CDR1 gene was significantly upregulated, and no significant change in expression of PDH1 gene was observed. Flow cytometric assays showed that FK506 reduced the efflux of fluconazole. Tacrolimus enhanced the susceptibility of fluconazole against resistant C. glabrata by reducing the expression levels of the ERG11 and SNQ2 genes and inhibiting fluconazole efflux.

Pre-existing invasive fungal infection is not a contraindication for allogeneic HSCT for patients with hematologic malignancies: a CIBMTR study

“…Alternatively, more frequent use of voriconazole in the cases may have led to higher levels of calcineurin inhibitors owing to drug-drug interactions, which may explain the lower rates of GVHD. Another possibility relates to recent observations that treatment of resistant candida has been augmented by adjunct therapy with calcineurin inhibitors 25,26 . These hypotheses cannot be tested, as information regarding the decision-making of the transplant teams on management in these cases is not available, as is often the case in retrospective registry studies.…”

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“…It can also reverse resistance phenotype generated by localized in the plasma membrane of S. cerevisiae Pdr5 protein or its homologue Cdr1p as in the case of C. albicans through direct binding to the transmembrane domain 10 (TMD10) [20]. It blocks the ability to cell detoxi ication, what was shown by low cytometric assays and restores susceptibility to azole drugs and other compounds that are substrates for Pdr5/Cdr1 protein [21]. This was clearly visible in the tests with tacrolimus, which was used only in a concentration equal to 5μM restored the phenotype of sensitivity to these two compounds.…”

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