Antifungal Activity, Synergism with Fluconazole or Amphotericin B and Potential Mechanism of Direct Current against <i>Candida albicans</i> Biofilms and Persisters

• Main Authors: Peihui Zou (Author), Jia Liu (Author), Peng Li (Author), Qingxian Luan (Author)
• Format: Book
• Published: MDPI AG, 2024-06-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antibiotics13060521; 2079-6382
• Keywords: direct current; <i>Candida albicans</i>; persisters; reactive oxygen species; superoxide dismutase; Therapeutics. Pharmacology; RM1-950
• Source: Antibiotics, Vol 13, Iss 6, p 521 (2024)

<i>Candida albicans</i>, as a notorious fungal pathogen, is associated with high morbidity and mortality worldwide due to its ability to form biofilms and persisters that can withstand currently available antifungals. Direct current (DC) has demonstrated a promising antimicrobial effect and synergistic effect with antimicrobials against various infections. Here, we first found DC exerted a killing effect on <i>C. albicans</i> planktonic and biofilm cells. Moreover, DC showed a synergistic effect with fluconazole (FLC) and amphotericin B (AMB). Notably, near-to-complete eradication of AMB-tolerant <i>C. albicans</i> biofilm persisters was achieved upon DC treatment. Next, the mechanism of action of DC was explored through mapping the genes and proteomic profiles of DC-treated <i>C. albicans</i>. The multi-omics analysis, quantitative real-time PCR and assay of reactive oxygen species (ROS) demonstrated DC exerted an antifungal effect on <i>C. albicans</i> by increasing cellular oxidative stress. As revealed by multiple analyses (e.g., protein assay based on absorbance at 280 nm and rhodamine 6G assay), DC was able to enhance membrane permeability, inhibit drug efflux and increase cellular FLC/AMB concentration of <i>C. albicans</i>, thereby mediating its synergism with the antifungals. Furthermore, DC inhibited superoxide dismutase 2 (SOD2) expression and manganese-containing SOD (Mn SOD) activity, leading to ROS production and enhanced killing of <i>C. albicans</i> biofilm persisters. The current findings demonstrate that the adjunctive use of DC in combination with antifungals is a promising strategy for effective control of <i>C. albicans</i> infections and management of antifungal resistance/tolerance in <i>Candida</i> biofilms.