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Reversal of azole resistance in Candida albicans by oridonin
Haisheng Chen1, Hui Li1, Cunxian Duan1
1Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, People's Republic of China.
Objectives:
Candida albicans is a yeast that causes fungal infections with high mortality and is typically resistant to azole drugs. To overcome this resistance, we explored the combined use of oridonin (ORI) and three azole drugs, namely fluconazole (FLC), itraconazole (ITR) and voriconazole (VOR). Azole-resistant C. albicans strains were obtained from cancer patients and the reversal of drug resistance in these strains was investigated.
Methods:
The synergistic antifungal activity of ORI and azole drugs was measured by checkerboard microdilution and time-kill assays. The resistance reversal mechanisms, namely inhibition of drug efflux and induction of apoptosis, were investigated by flow cytometry. Expression levels of the efflux pump-related genesCDR1 and CDR2 were assessed by RT-qPCR.
Results:
The efflux pump inhibition assay with ORI showed that the minimum inhibitory concentrations (MICs) of FLC (128-fold), ITR (64-fold) and VOR (250-fold) decreased significantly. Upregulation of genes encodingCDR1 and CDR2 was confirmed in the resistant strain. The sensitising effect of ORI on FLC in the treatment of C. albicans also included the promotion of apoptosis.
Conclusion:
We demonstrated that combining azoles with ORI exerted potent synergism and that ORI could promote sensitisation to azoles in azole-resistantC. albicans. The discovery that ORI can effectively inhibit drug efflux and promote apoptosis may provide new insights and therapeutic strategies to overcome increasing azole resistance in C. albicans.
Insights
Oridonin (ORI) combined with azole drugs effectively reverses azole resistance in Candida albicans by inhibiting drug efflux and promoting apoptosis. This combination offers a promising strategy against resistant fungal infections.
Area of Science:
- Mycology
- Pharmacology
- Infectious Diseases
Background:
- Candida albicans causes life-threatening infections and often exhibits resistance to azole antifungals.
- Rising azole resistance necessitates novel therapeutic approaches.
Purpose of the Study:
- To investigate the synergistic antifungal activity of oridonin (ORI) with azole drugs against azole-resistant Candida albicans.
- To elucidate the mechanisms by which ORI reverses azole resistance.
Main Methods:
- Checkerboard microdilution and time-kill assays to assess synergistic activity.
- Flow cytometry to investigate apoptosis induction and drug efflux inhibition.
- RT-qPCR to analyze the expression of efflux pump genes (CDR1, CDR2).
Main Results:
- Oridonin significantly reduced the minimum inhibitory concentrations (MICs) of fluconazole (128-fold), itraconazole (64-fold), and voriconazole (250-fold).
- Oridonin demonstrated efflux pump inhibition and promoted apoptosis in azole-resistant C. albicans.
- Upregulation of CDR1 and CDR2 genes was observed in resistant strains.
Conclusions:
- Combining oridonin with azoles exhibits potent synergism against azole-resistant Candida albicans.
- Oridonin's ability to inhibit drug efflux and induce apoptosis provides a novel strategy to combat azole resistance.
- This combination therapy holds potential for treating challenging C. albicans infections.