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<i>Candida albicans</i> is the main causal pathogen of fungal infections in human beings. Although diverse anti-<i>C. albicans</i> drugs have been explored, the drug resistance and side effects of these drugs are intensifying. Thus, it is urgent to explore new anti-<i>C. albicans</i> compounds from natural products. In this study, we identified trichoderma acid (TA), a compound from <i>Trichoderma spirale</i> with a strong inhibitory effect on <i>C. albicans</i>. Transcriptomic and iTRAQ-based proteomic analyses of TA-treated <i>C. albicans</i> in combination with scanning electronic microscopy and reactive oxygen species (ROS) detection were performed to investigate the potential targets of TA. The most significant differentially expressed genes and proteins after TA treatment were verified through Western blot analysis. Our results revealed that mitochondrial membrane potential, endoplasmic reticulum, ribosomes in the mitochondria, and cell walls were disrupted in TA-treated <i>C. albicans</i>, leading to the accumulation of ROS. The impaired enzymatic activities of superoxide dismutase further contributed to the increase in ROS concentration. The high concentration of ROS led to DNA damage and cell skeleton destruction. The expression levels of Rho-related GTP-binding protein RhoE (RND3), asparagine synthetase (ASNS), glutathione S-transferase, and heat shock protein 70 were significantly up-regulated in response to apoptosis and toxin stimulation. These findings suggest that RND3, ASNS, and supereoxide dismutase 5 are the potential targets of TA, as further demonstrated through Western blot analysis. The combination of transcriptomic, proteomic, and cellular analyses would provide clues for the anti-<i>C. albicans</i> mechanism of TA and the defensive response mechanism of <i>C. albicans</i>. TA is thus recognized as a promising new anti-<i>C. albicans</i> leading compound that alleviates the hazard of <i>C. albicans</i> infection in human beings.