Synergistic antifungal effects and mechanisms of amantadine hydrochloride combined with azole antifungal drugs on drug-resistant .

INTRODUCTION

The increasing resistance of () to conventional antifungal drugs poses a great challenge to the clinical treatment of infections caused by this yeast. Drug combinations are a potential therapeutic approach to overcome the drug- resistance of . This study explored the synergistic effects of amantadine hydrochloride (AMH) combined with azole antifungal drugs against drug-resistant and .

METHODS

The sensitivity of spp. to drugs was determined by the microdilution method. The effect of drugs on the efflux pump activity of was determined by the rhodamine 6G tracer method. The egg yolk agar plate method was used to determine the activity of extracellular phospholipase, a virulence factor. The model of  infection was used to test the efficacy of the combination therapy.

RESULTS

experiments showed that combinations of AMH with azole antifungal drugs had synergistic antifungal effects on planktonic cells of drug-resistant , with fractional inhibitory concentration index values of <0.5. The synergistic effects and mechanism of drug combinations with AMH were further studied using fluconazole (FLC) as a representative azole antifungal drug. , larvae were used to evaluate the antifungal efficacy of AMH +FLC. AMH + FLC treatment increased the survival rate of larvae infected with drug-resistant and reduced tissue invasion. Studies of the mechanism of synergy showed that AMH inhibited drug efflux pump activity in drug-resistant , and that AMH + FLC synergistically inhibited early biofilms and the extracellular phospholipase activity of drug-resistant .

CONCLUSION

This study provides strong evidence that combinations of non-antifungal drugs and antifungal drugs can effectively overcome drug-resistant infection. Both AMH and FLC are FDA-approved drugs, eliminating concerns about safety. Our findings provide a foundation for further clinical antifungal research.