Proteomic Analysis Reveals Proteins Involved in the Mode of Action of β-Citronellol Identified From Citrus hystrix DC. Leaf Against Candida albicans

Abstract

Candida albicans is a fungus that lives primarily on the mucosal surfaces of healthy humans, such as the oral cavity, vagina, and gastrointestinal tract. This commensal organism can be controlled by other microbiota, while certain conditions can increase the risk of C. albicans outgrowth and cause disease. Prevalence of the drug-resistant phenotype, as well as the severity of C. albicans infection in immunocompromised patients, presents a challenge for scientists to develop novel, effective treatment, and prevention strategies. β-Citronellol is an intriguing active compound of several plants that has been linked to antifungal activity, but data on the mechanism of action in terms of proteomic profiling are lacking. Here, β-citronellol identified from Citrus hystrix DC. leaf against C. albicans were evaluated. A proteomic approach was used to identify potential target proteins involved in the mode of action of β-citronellol. This study identified and discussed three protein groups based on the 126 major proteins that were altered in response to β-citronellol treatment, 46 of which were downregulated and 80 of which were upregulated. Significant protein groups include cell wall proteins (e.g., Als2p, Rbt1p, and Pga4p), cellular stress response enzymes (e.g., Sod1p, Gst2p, and Ddr48p), and ATP synthesis-associated proteins (e.g., Atp3p, Atp7p, Cox1p, and Cobp). Results demonstrated the complexities of protein interactions influenced by β-citronellol treatment and highlighted the potential of antifungal activity for future clinical and drug development research.

Insights into the anti‐Candida albicans properties of natural phytochemicals: An in vitro and in vivo investigation

“…An acyclic monoterpene, β ‐Citronellol, extensively studied and commonly observed in the EOs of plants such as rose, Pelargonium , and Citrus hystrix , displayed MIC and MFC values on C. albicans of 128 and 256 μg/mL, respectively. Moreover, their inhibitory effect on biofilms at 256 μg/mL was comparable to that of AMB treatment (Buakaew et al, 2022). Through proteomic analysis, Buakaew et al (2022) identified key proteomes with significant alterations, including cell wall proteins (Als2p and Rbt1p), oxidative stress response proteins (Sod1p and Gst2p), and ATP‐synthesis proteins (Atp3p and Cox1p).…”

“…Moreover, their inhibitory effect on biofilms at 256 μg/mL was comparable to that of AMB treatment (Buakaew et al, 2022). Through proteomic analysis, Buakaew et al (2022) identified key proteomes with significant alterations, including cell wall proteins (Als2p and Rbt1p), oxidative stress response proteins (Sod1p and Gst2p), and ATP‐synthesis proteins (Atp3p and Cox1p). Additionally, calmodulin (Cmd1p) expression increased with exposure to β ‐Citronellol, suggesting potential depletion of intracellular Ca 2+ , prompting yeast cells to activate the Ca 2+ compensation mechanism (Buakaew et al, 2022; Giuraniuc et al, 2023).…”

“…Within this review, 18 terpenoids exhibiting activity against C. albicans were documented. Among the active compounds isolated from EOs, thymol emerged as the primary prompting yeast cells to activate the Ca 2+ compensation mechanism (Buakaew et al, 2022;Giuraniuc et al, 2023). The APÀ1 bZIP tanscription factor, CAP1, implicated in oxidative stress and apoptosis in C. albicans, and was significantly upregulated (Buakaew et al, 2022;Kos et al, 2016).…”

“…Through proteomic analysis, Buakaew et al (2022) identified key proteomes with significant alterations, including cell wall proteins (Als2p and Rbt1p), oxidative stress response proteins (Sod1p and Gst2p), and ATP‐synthesis proteins (Atp3p and Cox1p). Additionally, calmodulin (Cmd1p) expression increased with exposure to β ‐Citronellol, suggesting potential depletion of intracellular Ca 2+ , prompting yeast cells to activate the Ca 2+ compensation mechanism (Buakaew et al, 2022; Giuraniuc et al, 2023). The AP−1 bZIP tanscription factor, CAP1 , implicated in oxidative stress and apoptosis in C. albicans , and was significantly upregulated (Buakaew et al, 2022; Kos et al, 2016).…”

“…Additionally, calmodulin (Cmd1p) expression increased with exposure to β ‐Citronellol, suggesting potential depletion of intracellular Ca 2+ , prompting yeast cells to activate the Ca 2+ compensation mechanism (Buakaew et al, 2022; Giuraniuc et al, 2023). The AP−1 bZIP tanscription factor, CAP1 , implicated in oxidative stress and apoptosis in C. albicans , and was significantly upregulated (Buakaew et al, 2022; Kos et al, 2016). CAP1 is upregulated in C. albicans cells treated with caspofungin (CAS), an antifungal drug specifically targeting β ‐glucan synthetase, suggesting that β ‐Citronellol may similarly interfere with cell wall production (Kelly et al, 2009).…”