Dataset Information

Fungal Cell Wall: Emerging Antifungals and Drug Resistance.

ABSTRACT: The cell wall is an essential component in fungal homeostasis. The lack of a covering wall in human cells makes this component an attractive target for antifungal development. The host environment and antifungal stress can lead to cell wall modifications related to drug resistance. Antifungals targeting the cell wall including the new ?-D-glucan synthase inhibitor ibrexafungerp and glycosyl-phosphatidyl Inositol (GPI) anchor pathway inhibitor fosmanogepix are promising weapons against antifungal resistance. The fosmanogepix shows strong in vitro activity against the multidrug-resistant species Candida auris, Fusarium solani, and Lomentospora prolificans. The alternative carbon sources in the infection site change the cell wall ?-D-glucan and chitin composition, leading to echinocandin and amphotericin resistance. Candida populations that survive echinocandin exposure develop tolerance and show high chitin content in the cell wall, while fungal species such as Aspergillus flavus with a higher ?-D-glucan content may show amphotericin resistance. Therefore understanding fungal cell dynamics has become important not only for host-fungal interactions, but also treatment of fungal infections. This review summarizes recent findings regarding antifungal therapy and development of resistance related to the fungal cell wall of the most relevant human pathogenic species.

SUBMITTER: Lima SL

PROVIDER: S-EPMC6881460 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Fungal Cell Wall: Emerging Antifungals and Drug Resistance.

Lima Soraia L SL Colombo Arnaldo L AL de Almeida Junior João N JN

Frontiers in microbiology 20191121

The cell wall is an essential component in fungal homeostasis. The lack of a covering wall in human cells makes this component an attractive target for antifungal development. The host environment and antifungal stress can lead to cell wall modifications related to drug resistance. Antifungals targeting the cell wall including the new β-D-glucan synthase inhibitor ibrexafungerp and glycosyl-phosphatidyl Inositol (GPI) anchor pathway inhibitor fosmanogepix are promising weapons against antifungal ...[more]

PMID: 31824443

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Project description:UnlabelledThe fungal cell wall confers cell morphology and protection against environmental insults. For fungal pathogens, the cell wall is a key immunological modulator and an ideal therapeutic target. Yeast cell walls possess an inner matrix of interlinked β-glucan and chitin that is thought to provide tensile strength and rigidity. Yeast cells remodel their walls over time in response to environmental change, a process controlled by evolutionarily conserved stress (Hog1) and cell integrity (Mkc1, Cek1) signaling pathways. These mitogen-activated protein kinase (MAPK) pathways modulate cell wall gene expression, leading to the construction of a new, modified cell wall. We show that the cell wall is not rigid but elastic, displaying rapid structural realignments that impact survival following osmotic shock. Lactate-grown Candida albicans cells are more resistant to hyperosmotic shock than glucose-grown cells. We show that this elevated resistance is not dependent on Hog1 or Mkc1 signaling and that most cell death occurs within 10 min of osmotic shock. Sudden decreases in cell volume drive rapid increases in cell wall thickness. The elevated stress resistance of lactate-grown cells correlates with reduced cell wall elasticity, reflected in slower changes in cell volume following hyperosmotic shock. The cell wall elasticity of lactate-grown cells is increased by a triple mutation that inactivates the Crh family of cell wall cross-linking enzymes, leading to increased sensitivity to hyperosmotic shock. Overexpressing Crh family members in glucose-grown cells reduces cell wall elasticity, providing partial protection against hyperosmotic shock. These changes correlate with structural realignment of the cell wall and with the ability of cells to withstand osmotic shock.ImportanceThe C. albicans cell wall is the first line of defense against external insults, the site of immune recognition by the host, and an attractive target for antifungal therapy. Its tensile strength is conferred by a network of cell wall polysaccharides, which are remodeled in response to growth conditions and environmental stress. However, little is known about how cell wall elasticity is regulated and how it affects adaptation to stresses such as sudden changes in osmolarity. We show that elasticity is critical for survival under conditions of osmotic shock, before stress signaling pathways have time to induce gene expression and drive glycerol accumulation. Critical cell wall remodeling enzymes control cell wall flexibility, and its regulation is strongly dependent on host nutritional inputs. We also demonstrate an entirely new level of cell wall dynamism, where significant architectural changes and structural realignment occur within seconds of an osmotic shock.

Dataset Information

Fungal Cell Wall: Emerging Antifungals and Drug Resistance.

Publications

Fungal Cell Wall: Emerging Antifungals and Drug Resistance.

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