Abstract:
Dermatophyte infections represent a significant public health concern, with an alarming
negative impact caused by unsuccessful therapeutic regimens. Natural products have been highlighted
as a promising alternative, due to their long-standing traditional use and increasing scientific
recognition. In this study, honokiol and magnolol, the main bioactives from Magnolia spp. bark, were
investigated for their antidermatophytic activity. The antifungal screening was performed using
dermatophyte standard strains and clinical isolates. The minimal inhibitory concentration (MIC)
and the minimal fungicidal concentration (MFC) were determined in accordance with EUCASTAFST
guidelines, with minor modifications. The effects on ergosterol biosynthesis were assessed in
Trichophyton rubrum cells by HPLC-DAD. Putative interactions with terbinafine against T. rubrum
were evaluated by the checkerboard method. Their impact on cells’ viability and pro-inflammatory
cytokines (IL-1 , IL-8 and TNF- ) was shown using an ex vivo human neutrophils model. Honokiol
and magnolol were highly active against tested dermatophytes, with MIC and MFC values of 8 and
16 mg/L, respectively. The mechanism of action involved the inhibition of ergosterol biosynthesis,
with accumulation of squalene in T. rubrum cells. Synergy was assessed for binary mixtures of
magnolol with terbinafine (FICI = 0.50), while honokiol-terbinafine combinations displayed only
additive effects (FICI = 0.56). In addition, magnolol displayed inhibitory effects towards IL-1 , IL-8
and TNF- released from lipopolysaccharide (LPS)-stimulated human neutrophils, while honokiol
only decreased IL-1 secretion, compared to the untreated control. Overall, honokiol and magnolol
acted as fungicidal agents against dermatophytes, with impairment of ergosterol biosynthesis.
