Anti- Malassezia Drug Candidates Based on Virulence Factors of Malassezia-Associated Diseases

Abstract

Malassezia is a lipophilic unicellular fungus that is able, under specific conditions, to cause severe cutaneous and systemic diseases in predisposed subjects. This review is divided into two complementary parts. The first one discusses how virulence factors contribute to Malassezia pathogenesis that triggers skin diseases. These virulence factors include Malassezia cell wall resistance, lipases, phospholipases, acid sphingomyelinases, melanin, reactive oxygen species (ROS), indoles, hyphae formation, hydrophobicity, and biofilm formation. The second section describes active compounds directed specifically against identified virulence factors. Among the strategies for controlling Malassezia spread, this review discusses the development of aryl hydrocarbon receptor (AhR) antagonists, inhibition of secreted lipase, and fighting biofilms. Overall, this review offers an updated compilation of Malassezia species, including their virulence factors, potential therapeutic targets, and strategies for controlling their spread. It also provides an update on the most active compounds used to control Malassezia species.

Keywords: Malassezia species; antifungals; drugs; natural compounds; virulence factors.

Figure 1

Malassezia virulence factors. Lipases, phospholipases and acid sphingomyelinases contribute to sebum lipid degradation into fatty acids which support Malassezia growth and cause skin diseases. Cell wall resistance, melanin, ROS, indoles, hyphae formation, hydrophobicity are involved in immune response modulation and contribute to Malassezia pathogenesis.

Scheme 1

Strategies to tackle Malassezia-related infections.

Figure 2

Chemical structures of betaine 1 and betaine derivatives 2 and 3 as described in [57].

Figure 3

Chemical structures of drugs classified as ergosterol biosynthesis inhibitor used by Nimura et al. [58] and Chimaphilin [59].

Figure 4

Biological results obtained used by Nimura et al. [58] and comparing the susceptibility of 5 drugs against a panel of strains.

Figure 5

(A) Main components from Zanthoxylum schinifolium Siebold & Zucc. essential oil (ZSEO); (B) M. restricta was treated with different concentrations of ZSEO for 1 h and cell membrane fluidity changes were measured; (C) M. restricta was treated with different concentrations of ZSEO for 4 h and then intracellular reactive oxygen species (ROS) were measured with fluorescence spectrophotometer, confocal laser scanning microscopy (CLSM) (D), and flow cytometry (E); (F) M. restricta was treated with different concentrations of ZSEO for 4 h and then observed with transmission electron microscope (TEM).

Figure 6

(A) C. albicans treated with scolopendin or melittin are stained with propidium iodide to detect increased membrane permeability. In black, the data from the blank. (B) The data represent the mean ± standard deviation for three independent experiments. **p < 0.05, *** p < 0.001 (Student’s t-test); (C) Depolarization of the membrane potential of C. albicans was detected by using DiSC3(5) dye. DiSC3(5) was added at t ¼ 50 s and the MIC of antimicrobial peptides at t ¼ 200 s to monitor fluorescence changes; (D) Potassium leakage after incubation with each AMP at its MIC in C. albicans. The error bars represent the standard deviation (SD).

Figure 7

(A) The chemical structures of PHMGH and amphotericin B; (B) The antifungal activity of PHMGH and amphotericin B; (C) Membrane depolarization detected by a potential-sensitive dye, DiSC3 (excitation: 622 nm, emission: 670 nm). DiSC3 was added at t = 1 min. The compounds were added at t = 6 min; (D) KD leakage from yeast cells treated with 1.25 mg/mL compounds for 2 h at 28 °C. The data display the mean ± standard deviation for three independent experiments; (E) Flow cytometric contour-plot analysis of yeast cells treated with PHMGH or amphotericin B. SSC (y-axis, log value) represents cell granularity, and FSC (x-axis) represents cell size; (F) The morphological change was visualized by a microscope.

Figure 8

(A) Chemical structures of four oligoguanidine polymer analogs: Polybutamethylene guanidine hydrochloride (C4); Polyhexamethylene guanidine hydrochloride (C6); Polyoctanethylene guanidine hydrochloride (C8); Poly(m-xylylene guanidine hydrochloride) (C8(benzene)); (B) Time-kill curve of synthesized Polymer C4, C6, C8, C8(benzene) against a model strain. Approximately 6.25 × 10⁶ CFU/mL bacterial cells were incubated, respectively, with 32 μg/mL polymer at 25 °C for 0.5, 1, 1.5, 2, and 2.5 h; (C) Hemolytic properties of synthesized oligoguanidine Polymer C4, C6, C8, C8(benzene) against human erythrocytes adapted from [66].

Figure 9

Chemical structures of effective antagonists of the AhR.

Figure 10

Structure of β-carbonic anhydrase inhibitors: acetazolamide AAZ and DTC derivative (DTC-5).

Figure 11

(A) Chemical structures of designed compounds adenine derivative from [82] and benzoxaboroles 2 and 6; (B) Predicted binding modes of 2 (light blue) and 6 (green), within MgCA active sites. The nitro group of 2 established lipophilic contacts with B:A111, B:L132, and B:G107. The ureido group of 6 was involved in a three-center H-bond with B:G107.(Reprinted with permission from [84]. Copyright 2023 American Chemical Society); (C) Proposed binding of aromatic boronic acids to β-CAs. In β-CAs, the Zn(II) is coordinated by one His and two Cys residues (Can2 numbering system used in C), and the fourth ligand being a water molecule/hydroxide ion, which being a strong nucleophile may react with the electrophilic boronic acid leading to the adduct.

Figure 12

Design of seleno compounds with selective antifungal activity against M. pachydermatis, adapted from [86].

Figure 13

(A) Schematic representation of the binding mode of phenol into the MgCA active sites; (B) Hydrophobic surface of binding site receptor area; hydrophobicity increases from blue to brown; (C) Schematic representation of the aligned derivatives in the hydrophobic pocket.

Figure 14

Timeline discovery of new chemical class as inhibitors of Malassezia β-carbonic anhydrases.

Figure 15

(A) Determination of minimal inhibitory concentration of embelin against M. furfur (MTCC 1374). Error bars and * symbol represent SD and statistical significance (* p < 0.05), respectively; (B) Effect of embelin on the secreted lipase of Malassezia spp.

Figure 16

(A) Chemical structures of the compounds involved; (B) Docked binding poses of the compounds involved. (B) Superimposition of RHC 80267 with compounds 1, 4, and 5, the lipase pocket is displayed as a charged surface. Docked binding poses of the compounds involved. (A) Superimposition of RHC 80267 with compounds 1, 4, and 5, lipase pocket is shown as a charged surface. Binding poses of (C) compound 1 (green) and 4 (purple). Compounds are shown in sticks, interacting residues in SMG1 are depicted in lines, and hydrogen bonds are represented in dashed red lines.

Figure 17

(A) M. furfur growth on modified Dixon agar after being treated with various concentrations ranging from 0.0312 to 0.5 mg/mL of ketoconazole (K) and fermented O. sanctum (FE) for 72 h at 32 ± 2 °C; (B) NF-kB levels after being treated with indomethacin (IND), bio-fermented O. sanctum extract (FE) in U937 cells for 48 h detected by Western blot analysis. A vehicle control (VC) was U937 cells treated with DMSO (1% v/v). *** p < 0.001.

Figure 18

(A) Sargassum muticum extraction flowchart; (B) Antioxidant capacity of Sargassum muticum fractions adapted from [94].

Figure 19

(A) Chemical structure and lipophily of main components of Dittrichia viscosa L. leaves lipid extract; (B) Elastase inhibition activity (%) of D. viscosa lipid extract at different concentration (1, 5, and 10 mg/mL) compared with EGCG.

Figure 20

(A) Cecropin A–magainin 2 (CA–MA) hybrid peptide analog P5 inhibits the expression of IL-8 (A) and Toll-like receptor 2 (TLR2); (B) induced by M. furfur infection in normal human keratinocytes from [103]. * p < 0.001.

Figure 21

Apoptosis induced by Tambjamine I and J alkaloids as adapted from [113]. Negative control (C) was treated with the vehicle used for diluting the tested substance. Doxorubicin (D; 0.3 mg/mL) was used as positive control. * p < 0.001.

Figure 22

Chemical structures of main components from A. galanta n-hexane extract.

Figure 23

Effects of Fraction V on M. furfur at 1/2 MIC. (A) Colony morphology of M. furfur CBS 1878 on YPD-Tween and IM agar. The plates were incubated at 30 °C. Bars corresponding to 1 mm; (B) Growth kinetics of M. furfur CBS 1878 cultured in YPD-Tween broth and IM broth. Values represent the mean ± SD of OD at 600 nm (n = 3 in each group). Asterisks indicate statistical significance between groups (* p < 0.05); (C) Cell morphology of the yeast phase of M. furfur CBS 1878 cultured in IM broth (magnification × 630). Bars corresponding to 20 μm; (D) Cell morphology of the mycelial phase of M. furfur CBS 1878 grown in IM broth (magnification × 630). Bars represent 10 μm. Black arrows indicate multiple massive vacuoles. White arrows illustrate intense fluorescence of chitin-rich bud scars or hyphal tips.

Figure 24

Structures of HIT compounds 2a and 4a and ketoconazole with some structure–activity relationships and logP (adapted from [122]).

Figure 25

Chemical structures of SB-1.

Figure 26

Major components of liquid and vapor phases of Artemisia annua essential oil.

Figure 27

Chemical structures of components of essential oils studied by [131].

Figure 28

Timeline of reports dealing with anti-Malassezia drug candidates from 2001 to nowadays.

Figure 29

Repartition of the reported mode of action for active drugs.