AUTHOR=Qian Weidong , Li Xinchen , Liu Qiming , Lu Jiaxing , Wang Ting , Zhang Qian 

TITLE=Antifungal and Antibiofilm Efficacy of Paeonol Treatment Against Biofilms Comprising Candida albicans and/or Cryptococcus neoformans

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2022.884793

DOI=10.3389/fcimb.2022.884793

ISSN=2235-2988

ABSTRACT=<p>Fungal populations are commonly found in natural environments and present enormous health care challenges, due to increased resistance to antifungal agents. Paeonol exhibits antifungal activities; nevertheless, the antifungal and antibiofilm activities of paeonol against <italic>Candida albicans</italic> and <italic>Cryptococcus neoformans</italic> remain largely unexplored. Here, we aimed to evaluate the antifungal and antibiofilm activities of paeonol against <italic>C. albicans</italic> and/or <italic>C. neoformans</italic> (i.e., against mono- or dual-species). The minimum inhibitory concentrations (MICs) of paeonol for mono-species comprising <italic>C. albicans</italic> or <italic>C. neoformans</italic> were 250 μg ml<sup>−1</sup>, whereas the MIC values of paeonol for dual-species were 500 μg ml<sup>−1</sup>. Paeonol disrupted cell membrane integrity and increased the influx of gatifloxacin into cells of mono- and dual-species cells, indicating an antifungal mode of action. Moreover, paeonol at 8 times the MIC damaged mono- and dual-species cells within <italic>C. albicans</italic> and <italic>C. neoformans</italic> biofilms, as it did planktonic cells. In particular, at 4 and 8 mg ml<sup>−1</sup>, paeonol efficiently dispersed preformed 48-h biofilms formed by mono- and dual-species cells, respectively. Paeonol inhibited effectively the yeast-to-hyphal-form transition of <italic>C. albicans</italic> and impaired capsule and melanin production of <italic>C. neoformans</italic>. The addition of 10 MIC paeonol to the medium did not shorten the lifespan of <italic>C. elegans</italic>, and 2 MIC paeonol could effectively protect the growth of <italic>C. albicans</italic> and <italic>C. neoformans</italic>-infected <italic>C. elegans</italic>. Furthermore, RNA sequencing was employed to examine the transcript profiling of <italic>C. albicans</italic> and <italic>C. neoformans</italic> biofilm cells in response to 1/2 MIC paeonol. RNA sequencing data revealed that paeonol treatment impaired biofilm formation of <italic>C. albicans</italic> by presumably downregulating the expression level of initial filamentation, adhesion, and growth-related genes, as well as biofilm biosynthesis genes, whereas paeonol inhibited biofilm formation of <italic>C. neoformans</italic> by presumably upregulating the expression level of ergosterol biosynthesis-related genes. Together, the findings of this study indicate that paeonol can be explored as a candidate antifungal agent for combating serious single and mixed infections caused by <italic>C. albicans</italic> and <italic>C. neoformans</italic>.</p>