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Global burden of fungal infections and related health risk has accelerated at an incredible pace, and multidrug resistance emergency aggravates the need for the development of new effective strategies.  Candida albicans  is clinically the most ubiquitous pathogenic fungus that leads to high incidence and mortality in immunocompromised patients. Antimicrobial peptides (AMPs), in this context, represent promising alternatives having potential to be exploited for improving human health. In our previous studies, a Cecropin-4-derived peptide named C18 was found to possess a broader antibacterial spectrum after modification and exhibit significant antifungal activity against  C. albicans . In this study, C18 shows antifungal activity against  C. albicans  or non- albicans Candida  species with a minimum inhibitory concentration (MIC) at 4∼32 μg/ml, and clinical isolates of fluconazole (FLZ)-resistance C.  tropicalis  were highly susceptible to C18 with MIC value of 8 or 16 μg/ml. Additionally, C18 is superior to FLZ for killing planktonic  C. albicans  from inhibitory and killing kinetic curves. Moreover, C18 could attenuate the virulence of  C. albicans , which includes damaging the cell structure, retarding hyphae transition, and inhibiting biofilm formation. Intriguingly, in the  Galleria mellonella  model with  C. albicans  infection, C18 could improve the survival rate of  G. mellonella  larvae to 70% and reduce  C. albicans  load from 5.01 × 10 7  to 5.62 × 10 4  CFU. For mechanistic action of C18, the level of reactive oxygen species (ROS) generation and cytosolic Ca 2 +  increased in the presence of C18, which is closely associated with mitochondrial dysfunction. Meanwhile, mitochondrial membrane potential (△Ψm) loss and ATP depletion of  C. albicans  occurred with the treatment of C18. We hypothesized that C18 might inhibit  C. albicans  via triggering mitochondrial dysfunction driven by ROS generation and Ca 2 +  accumulation. Our observation provides a basis for future research to explore the antifungal strategies and presents C18 as an attractive therapeutic candidate to be developed to treat candidiasis.

A Cecropin-4 Derived Peptide C18 Inhibits Candida albicans by Disturbing Mitochondrial Function