Combatting Fungal Infections: Advances in Antifungal Polymeric Nanomaterials.

Fungal pathogens cause over 6.5 million life-threatening systemic infections annually, with mortality rates ranging from 20 to 95%, even with medical intervention. The World Health Organization has recently emphasized the urgent need for new antifungal drugs.

A synthetic peptide mimic kills Candida albicans and synergistically prevents infection.

More than two million people worldwide are affected by life-threatening, invasive fungal infections annually. Candida species are the most common cause of nosocomial, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited.

Bacteria-derived short-chain fatty acids as potential regulators of fungal commensalism and pathogenesis.

The human gastrointestinal microbiome encompasses bacteria, fungi, and viruses forming complex bionetworks which, for organismal health, must be in a state of homeostasis. An important homeostatic mechanism derives from microbial competition, which maintains the relative abundance of microbial species in a healthy balance. Microbes compete for nutrients and secrete metabolites that inhibit other microbes.

Mimicking Charged Host-Defense Peptides to Tune the Antifungal Activity and Biocompatibility of Amphiphilic Polymers.

Invasive fungal infections impose a substantial global health burden. They cause more than 1.5 million deaths annually and are insufficiently met by the currently approved antifungal drugs.

Effect of Star Topology Versus Linear Polymers on Antifungal Activity and Mammalian Cell Toxicity.

The global increase in invasive fungal infections and the emergence of drug-resistant strains demand the urgent development of novel antifungal drugs. In this context, synthetic polymers with diverse compositions, mimicking natural antimicrobial peptides, have shown promising potential for combating fungal infections. This study investigates how altering polymer end-groups and topology from linear to branched star-like structures affects their efficacy against Candida spp.

Architecture of the dynamic fungal cell wall.

The fungal cell wall is essential for growth and survival, and is a key target for antifungal drugs and the immune system. The cell wall must be robust but flexible, protective and shielding yet porous to nutrients and membrane vesicles and receptive to exogenous signals. Most fungi have a common inner wall skeleton of chitin and β-glucans that functions as a flexible viscoelastic frame to which a more diverse set of outer cell wall polymers and glycosylated proteins are attached.

Human gut bifidobacteria inhibit the growth of the opportunistic fungal pathogen Candida albicans.

The human gut microbiota protects the host from invading pathogens and the overgrowth of indigenous opportunistic species via a process called colonization resistance. Here, we investigated the antagonistic activity of human gut bacteria towards Candida albicans, an opportunistic fungal pathogen that can cause severe infections in susceptible individuals. Coculture batch incubations of C.

Crosstalk between the calcineurin and cell wall integrity pathways prevents chitin overexpression in Candida albicans.

Echinocandins such as caspofungin are frontline antifungal drugs that compromise β-1,3 glucan synthesis in the cell wall. Recent reports have shown that fungal cells can resist killing by caspofungin by upregulation of chitin synthesis, thereby sustaining cell wall integrity (CWI). When echinocandins are removed, the chitin content of cells quickly returns to basal levels, suggesting that there is a fitness cost associated with having elevated levels of chitin in the cell wall.

Rational Design of an Antifungal Polyacrylamide Library with Reduced Host-Cell Toxicity.

Life-threatening invasive fungal infections represent an urgent threat to human health worldwide. The limited set of antifungal drugs has critical constraints such as resistance development and/or adverse side effects. One approach to overcome these limitations is to mimic naturally occurring antifungal peptides called defensins.

Scalar nanostructure of the cell wall; a molecular, cellular and ultrastructural analysis and interpretation.

Despite the importance of fungal cell walls as the principle determinant of fungal morphology and the defining element determining fungal interactions with other cells, few scalar models have been developed that reconcile chemical and microscopic attributes of its structure. The cell wall of the fungal pathogen is comprised of an amorphous inner skeletal layer of β(1,3)- and β(1,6)-glucan and chitin and an outer fibrillar layer thought to be dominated by highly mannosylated cell wall proteins. The architecture of these two layers can be resolved at the electron microscopy level, but the visualised structure of the wall has not yet been defined precisely in chemical terms.

The Viscoelastic Properties of the Fungal Cell Wall Allow Traffic of AmBisome as Intact Liposome Vesicles.

The fungal cell wall is a critically important structure that represents a permeability barrier and protective shield. We probed and with liposomes containing amphotericin B (AmBisome), with or without 15-nm colloidal gold particles. The liposomes have a diameter of 60 to 80 nm, and yet their mode of action requires them to penetrate the fungal cell wall to deliver amphotericin B to the cell membrane, where it binds to ergosterol.

Adaptation of Candida albicans to environmental pH induces cell wall remodelling and enhances innate immune recognition.

Candida albicans is able to proliferate in environments that vary dramatically in ambient pH, a trait required for colonising niches such as the stomach, vaginal mucosal and the GI tract. Here we show that growth in acidic environments involves cell wall remodelling which results in enhanced chitin and β-glucan exposure at the cell wall periphery. Unmasking of the underlying immuno-stimulatory β-glucan in acidic environments enhanced innate immune recognition of C.

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence.

Efficient carbon assimilation is critical for microbial growth and pathogenesis. The environmental yeast Saccharomyces cerevisiae is "Crabtree positive", displaying a rapid metabolic switch from the assimilation of alternative carbon sources to sugars. Following exposure to sugars, this switch is mediated by the transcriptional repression of genes (carbon catabolite repression) and the turnover (catabolite inactivation) of enzymes involved in the assimilation of alternative carbon sources.

Cell wall protection by the Candida albicans class I chitin synthases.

Candida albicans has four chitin synthases from three different enzyme classes which deposit chitin in the cell wall, including at the polarized tips of growing buds and hyphae, and sites of septation. The two class I enzymes, Chs2 and Chs8, are responsible for most of the measurable chitin synthase activity in vitro, but their precise biological functions in vivo remain obscure. In this work, detailed phenotypic analyses of a chs2Δchs8Δ mutant have shown that C.

Fungal chitin dampens inflammation through IL-10 induction mediated by NOD2 and TLR9 activation.

Chitin is an essential structural polysaccharide of fungal pathogens and parasites, but its role in human immune responses remains largely unknown. It is the second most abundant polysaccharide in nature after cellulose and its derivatives today are widely used for medical and industrial purposes. We analysed the immunological properties of purified chitin particles derived from the opportunistic human fungal pathogen Candida albicans, which led to the selective secretion of the anti-inflammatory cytokine IL-10.

The Mnn2 mannosyltransferase family modulates mannoprotein fibril length, immune recognition and virulence of Candida albicans.

The fungal cell wall is the first point of interaction between an invading fungal pathogen and the host immune system. The outer layer of the cell wall is comprised of GPI anchored proteins, which are post-translationally modified by both N- and O-linked glycans. These glycans are important pathogen associated molecular patterns (PAMPs) recognised by the innate immune system.

Cell wall stress induces alternative fungal cytokinesis and septation strategies.

In fungi, as with all walled organisms, cytokinesis followed by septation marks the end of the cell cycle and is essential for cell division and viability. For yeasts, the septal cross-wall comprises a ring and primary septal plate composed of chitin, and a secondary septum thickened with β(1,3)-glucan. In the human pathogen Candida albicans, chitin synthase enzyme Chs1 builds the primary septum that is surrounded by a chitin ring made by Chs3.

A systems biology analysis of long and short-term memories of osmotic stress adaptation in fungi.

Background: Saccharomyces cerevisiae senses hyperosmotic conditions via the HOG signaling network that activates the stress-activated protein kinase, Hog1, and modulates metabolic fluxes and gene expression to generate appropriate adaptive responses. The integral control mechanism by which Hog1 modulates glycerol production remains uncharacterized. An additional Hog1-independent mechanism retains intracellular glycerol for adaptation.

Combinatorial stresses kill pathogenic Candida species.

Pathogenic microbes exist in dynamic niches and have evolved robust adaptive responses to promote survival in their hosts. The major fungal pathogens of humans, Candida albicans and Candida glabrata, are exposed to a range of environmental stresses in their hosts including osmotic, oxidative and nitrosative stresses. Significant efforts have been devoted to the characterization of the adaptive responses to each of these stresses.

Rapid detection of aneuploidy following the generation of mutants in Candida albicans.

Techniques used to generate mutants in Candida albicans commonly result in additional and undesired genetic rearrangements. Detection of aneuploidy is, therefore, an important step forward in the quality control of mutant phenotypes. In this chapter, we describe how to extract genomic DNA and perform a quantitative multiplex PCR to compare the karyotype of any mutant strain to that of its parent and allow the detection of any unwanted aneuploidy.

The dectin-1/inflammasome pathway is responsible for the induction of protective T-helper 17 responses that discriminate between yeasts and hyphae of Candida albicans.

In the mucosa, the immune pathways discriminating between colonizing and invasive Candida, thus inducing tolerance or inflammation, are poorly understood. Th17 responses induced by Candida albicans hyphae are central for the activation of mucosal antifungal immunity. An essential step for the discrimination between yeasts and hyphae and induction of Th17 responses is the activation of the inflammasome by C.

Recognition and blocking of innate immunity cells by Candida albicans chitin.

Chitin is a skeletal cell wall polysaccharide of the inner cell wall of fungal pathogens. As yet, little about its role during fungus-host immune cell interactions is known. We show here that ultrapurified chitin from Candida albicans cell walls did not stimulate cytokine production directly but blocked the recognition of C.

Chitin synthesis and fungal pathogenesis.

Chitin is an essential part of the carbohydrate skeleton of the fungal cell wall and is a molecule that is not represented in humans and other vertebrates. Complex regulatory mechanisms enable chitin to be positioned at specific sites throughout the cell cycle to maintain the overall strength of the wall and enable rapid, life-saving modifications to be made under cell wall stress conditions. Chitin has also recently emerged as a significant player in the activation and attenuation of immune responses to fungi and other chitin-containing parasites.

Phosphorylation regulates polarisation of chitin synthesis in Candida albicans.

The ability to undergo polarised cell growth is fundamental to the development of almost all walled organisms. Fungi are characterised by yeasts and moulds, and both cellular forms have been studied extensively as tractable models of cell polarity. Chitin is a hallmark component of fungal cell walls.

Dissection of the Candida albicans class I chitin synthase promoters.

Maintenance of the integrity of the cell wall in fungi is essential. One mechanism that cells use to maintain cell wall integrity in response to cell wall damage is to up-regulate chitin synthesis. In Candida albicans, the PKC cell wall integrity, Ca(2+)/calcineurin and high osmolarity glycerol (HOG) signalling pathways co-ordinately regulate chitin synthesis in response to cell wall stress.