11g, a Potent Antifungal Candidate, Enhances Candida albicans Immunogenicity by Unmasking β-Glucan in Fungal Cell Wall

Abstract

In the course of optimizing GPI biosynthesis inhibitors, we designed and synthetized a 2-aminonicotinamide derivative named 11g. After evaluating the antifungal activity of compound 11g in vitro, we investigated the influences of 11g on fungi immunogenicity. In addition, we also took advantage of murine systemic candidiasis model to investigate the protective effects of 11g in vivo. Results show that 11g exhibited potent antifungal activity both in vitro and in vivo. Further study shows that 11g caused the unmasking of fungi β-glucan layer, leading to stronger immune responses in macrophages through Dectin-1. These results suggest that 11g is a very promising antifungal candidate, which assists in eliciting stronger immune responses to help host immune system disposing pathogens. The discovery of 11g might expand the toolbox of fungal infection treatment.

Cek1 regulates ß(1,3)-glucan exposure through calcineurin effectors in Candida albicans

“…All three contain putative secretion signals and two of the three (PGA13 and FGR41) have predicted glycosylphosphatidylinositol anchors in their sequences. This observation fits the model that alterations in outer cell wall components are capable of affecting ß(1,3)-glucan exposure [26][27][28] and encouraged further exploration of these targets.…”

“…Similarly, Histoplasma capsulatum masks ß(1,3)-glucan under a layer of α-glucan, and further reduces unmasked foci via expression of the glycosylhydrolyase Eng1 [24,25]. Candida albicans covers ß(1,3)-glucan in its cell wall under an outer layer of densely populated mannoproteins, and mutations that prevent proper glycosylphosphatidylinositol (GPI)-anchored protein synthesis or protein mannosylation induce unmasking [26][27][28]. Similarly, C. albicans senses environmental signals and stressors, such as lactate [29,30], acidic pH [31,32], hypoxia [33], and iron-replete environments [34] and responds by further altering ß(1,3)-glucan exposure.…”

“…Similarly, Histoplasma capsulatum masks ß(1,3)-glucan under a layer of α-glucan, and further reduces unmasked foci via expression of the glycosylhydrolyase Eng1 [ 24 , 25 ]. Candida albicans covers ß(1,3)-glucan in its cell wall under an outer layer of densely populated mannoproteins, and mutations that prevent proper glycosylphosphatidylinositol (GPI)-anchored protein synthesis or protein mannosylation induce unmasking [ 26 – 28 ]. Similarly, C .…”

Combined Transcriptome and Metabolome Analysis Reveals That the Potent Antifungal Pyrylium Salt Inhibits Mitochondrial Complex I in Candida albicans

“…Clinical C. albicans strains UCA3, UCA21, UCA32, UCA42, UCA103, and UCA385 were isolated from patients with fungal infections in the Dermatology Department of Changhai Hospital ( 36 ). C. albicans strain SC5314 and mitochondrial complexes-deficient mutants ( aep1 Δ/Δ, coe1 Δ/Δ, coe2 Δ/Δ, qce1 Δ/Δ, nue 1Δ/Δ, nue2 Δ/Δ, nuo3 Δ/Δ, nuo4 Δ/Δ, pet111 Δ/Δ) were provided by William A. Fonzi ( 9 ).…”

When Is It Appropriate to Take Off the Mask? Signaling Pathways That Regulate ß(1,3)-Glucan Exposure in Candida albicans

“…Genetic deletion of GPI7, an essential protein in GPI anchor synthesis, blocks the decoration of the second mannose in the glycan with phosphoethanolamine and subsequently unmasks ß(1,3)-glucan (Shen et al, 2015). Additionally, chemical inhibition of GPI anchor synthesis with gepinacin, which inhibits the activity of a critical acyltransferase Gwt1, or with the 2-aminonicitinomide derivative 11g, increased ß(1,3)-glucan exposure in the cell wall and resulted in increased cytokine production from murine macrophages (Umemura et al, 2003;Mclellan et al, 2012;Ni et al, 2017;Huang et al, 2020). In the case of 11g treatment, this also corresponded with increased survival and reduced kidney fungal burden during systemic infection in mice (Huang et al, 2020).…”