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

Chao-Qin Sun; Jian Peng; Long-Bing Yang; Zheng-Long Jiao; Luo-Xiong Zhou; Ru-Yu Tao; Li-Juan Zhu; Zhu-Qing Tian; Ming-Jiao Huang; Guo Guo

doi:10.3389/fmicb.2022.872322

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

Front Microbiol. 2022 Apr 19:13:872322. doi: 10.3389/fmicb.2022.872322. eCollection 2022.

Authors

Chao-Qin Sun^{1

2}, Jian Peng^{1

3}, Long-Bing Yang¹, Zheng-Long Jiao^{1

4}, Luo-Xiong Zhou^{1

3}, Ru-Yu Tao⁵, Li-Juan Zhu¹, Zhu-Qing Tian¹, Ming-Jiao Huang¹, Guo Guo^{1

3

4}

Affiliations

¹ The Key and Characteristic Laboratory of Modern Pathogen Biology, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China.
² Center of Laboratory Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
³ Key Laboratory of Environmental Pollution Monitoring and Disease Control, Guizhou Medical University, Ministry of Education, Guiyang, China.
⁴ Translational Medicine Research Center, Guizhou Medical University, Guiyang, China.
⁵ Department of Laboratory Medicine, The Second Affiliated Hospital of Guizhou Medical University, Kaili, China.

Abstract

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 × 10⁷ to 5.62 × 10⁴ 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.

Keywords: Candida albicans; G. mellonella; ROS; antifungal activity; cecropin-4 derived peptide; mitochondrial dysfunction.