The synergistic antifungal effects of sodium phenylbutyrate combined with azoles against Candida albicans via the regulation of the Ras–cAMP–PKA signalling pathway and virulence

Abstract

The pathogenic fungus Candida albicans is one of the most commonly clinically isolated fungal species, and its resistance to the antifungal drug fluconazole is known to be increasing. In this paper, we sought to characterize the effect of sodium phenylbutyrate used alone or in combination with azoles against resistant C. albicans. The minimum inhibitory concentrations and sessile minimum inhibitory concentrations were determined to explore the synergistic mechanism. The results showed that sodium phenylbutyrate exerted clear antifungal activity and that the combination of sodium phenylbutyrate and azoles functioned synergistically to combat resistant C. albicans. In our study of the mechanism, we initially found that the combination therapy resulted in the inhibition of hypha growth, the increased penetration of fluconazole through C. albicans biofilm, and the decreased expression of hyphae-related genes and the upstream regulatory genes (CYR1 and TPK2) of the Ras–cAMP–PKA signalling pathway, as determined by RT–PCR. In addition, the combination treatment decreased the extracellular phospholipase activities and the expression of aspartyl proteinase genes (SAP1–SAP3). The synergistic antifungal effects of the combination of sodium phenylbutyrate and azoles against resistant C. albicans was mainly based on the regulation of the Ras–cAMP–PKA signalling pathway, hyphae-related genes, and virulence factors.

Anticandidal Activity of Omiganan and Its Retro Analog Alone and in Combination with Fluconazole

“…Similar, although not yet understood, synergistic or additive effects of fluconazole with various AMPs against Candida spp. strains (especially FLC-resistant fungi) were reported [30][31][32][33][34][35]. It was claimed that combination of different compounds as described above could be one of the most promising approach as to develop alternative therapy against multidrug resistant or biofilmforming yeast-like fungi.…”

“…On the basis of this development, it has been postulated that both compounds (Omiganan and retro-Omiganan) could effectively be used in the treatment of Candida infections associated with biofilm. Moreover, there are few studies that indicate synergistic anti-Candida effect of combination of azoles (e.g., fluconazole) with various AMPs [30][31][32][33][34][35]. This effect could probably be associated with different mechanisms of action of both groups of compounds.…”

The regulation of hyphae growth in Candida albicans

“…cAMP-PKA (cyclic adenosine monophosphateprotein kinase A) pathway The cAMP-PKA pathway plays a key role in C. albicans growth, morphogenesis, glycogen synthesis, mitochondrial activity, and energy metabolism [51][52][53]. cAMP is necessary for the activation of PKA pathway in response to various environmental stimuli, including serum, N-Acetylglucosamine (GlcNAc), amino acids, and carbon dioxide.…”

Antifungal Activity of Linear and Disulfide-Cyclized Ultrashort Cationic Lipopeptides Alone and in Combination with Fluconazole Against Vulvovaginal Candida spp.

“…In the NCAC group, indifference remained the most frequent result (64%). The literature has described the possibility of a favorable antifungal effect due to combinations of uconazole with various AMPs [34][35][36][37][38][39] . The use of compounds with different mechanisms of action is generally recommended.…”