scholarly journals Dectin-1-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Suresh Ambati ◽  
Aileen R. Ferarro ◽  
S. Earl Kang ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Cell Walls ◽  
Fungal Pathogens ◽  
Antifungal Drugs ◽  
Beta Glucan ◽  
Fungal Cell ◽  
Content Type ◽  
Current Therapies ◽  
Mammalian Protein ◽  
Fungal Cell Walls

The fungus Aspergillus fumigatus causes pulmonary invasive aspergillosis resulting in nearly 100,000 deaths each year. Patients are often treated with antifungal drugs such as amphotericin B (AmB) loaded into liposomes (AmB-LLs), but all antifungal drugs, including AmB-LLs, have serious limitations due to human toxicity and insufficient fungal cell killing. Even with the best current therapies, 1-year survival among patients with invasive aspergillosis is only 25 to 60%. Hence, there is a critical need for improved antifungal therapeutics. Dectin-1 is a mammalian protein that binds to beta-glucan polysaccharides found in nearly all fungal cell walls. We coated AmB-LLs with Dectin-1 to make DEC-AmB-LLs. DEC-AmB-LLs bound strongly to fungal cells, while AmB-LLs had little affinity. DEC-AmB-LLs killed or inhibited A. fumigatus 10 times more efficiently than untargeted liposomes, decreasing the effective dose of AmB. Dectin-1-coated drug-loaded liposomes targeting fungal pathogens have the potential to greatly enhance antifungal therapeutics.

scholarly journals Targeted antifungal liposomes

2019 ◽  
Author(s):  
Suresh Ambati ◽  
Aileen R. Ferarro ◽  
S. Earl Khang ◽  
Xiaorong Lin ◽  
Michelle Momany ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Cell Walls ◽  
Fungal Pathogens ◽  
Antifungal Drugs ◽  
Human Toxicity ◽  
Beta Glucan ◽  
Fungal Cell ◽  
Order Of Magnitude ◽  
One Year ◽  
Fungal Cell Walls

AbstractAspergillus species cause pulmonary invasive aspergillosis resulting in nearly a hundred thousand deaths each year. Patients at the greatest risk of developing life-threatening aspergillosis have weakened immune systems and/or various lung disorders. Patients are treated with antifungals such as amphotericin B (AmB), casofungin acetate, or triazoles (itraconazole, voriconazole etc.), but these antifungal agents have serious limitations due to lack of sufficient fungicidal effect and human toxicity. Liposomes with AmB intercalated into the lipid membrane (AmBisomes, AmB-LLs), have several-fold reduced toxicity compared to detergent solubilized drug. However, even with the current antifungal therapies, one-year survival among patients is only 25 to 60%. Hence, there is a critical need for improved antifungal therapeutics.Dectin-1 is a mammalian innate immune receptor in the membrane of some leukocytes that binds as a dimer to beta-glucans found in fungal cell walls, signaling fungal infection. Using a novel protocol, we coated AmB-LLs with Dectin-1’s beta-glucan binding domain to make DEC-AmB-LLs. DEC-AmB-LLs bound rapidly, efficiently, and with great strength Aspergillus fumigatus and to Candida albicans and Cryptococcus neoformans, highly divergent fungal pathogens of global importance. By contrast, un-targeted AmB-LLs and BSA-coated BSA-AmB-LLs showed 200-fold lower affinity for fungal cells. DEC-AmB-LLs reduced the growth and viability of A. fumigatus an order of magnitude more efficiently than untargeted control liposomes delivering the same concentrations of AmB, in essence increasing the effective dose of AmB. Future efforts will focus on examining pan-antifungal targeted liposomal drugs in animal models of disease.TweetWe coated anti-fungal drug loaded liposomes to fungal cell walls with a beta-glucan binding protein and thereby increased drug effectiveness by an order of magnitude.ImportanceThe fungus Aspergillus fumigatus causes pulmonary invasive aspergillosis resulting in nearly a hundred thousand deaths each year. Patients are often treated with antifungal drugs such as amphotericin B loaded into liposomes, AmB-LLs, but all antifungal drugs including AmB-LLs have serious limitations due to human toxicity and insufficient fungal cell killing. Even with the best current therapies, one-year survival among patients with invasive aspergillosis is only 25 to 60%. Hence, there is a critical need for improved antifungal therapeutics.Dectin-1 is a mammalian protein that binds to beta-glucan polysaccharides found in nearly all fungal cell walls. We coated AmB-LLs with Dectin-1 to make DEC-AmB-LLs. DEC-AmB-LLs bond strongly to fungal cells, while AmB-LLs had little affinity. DEC-AmB-LLs killed or inhibited A. fumigatus ten times more efficiently than untargeted lipsomes, increasing the effective dose of AmB. Dectin-1 coated liposomes targeting fungal pathogens have the potential to greatly enhance antifungal therapeutics.

scholarly journals Jerveratrum-Type Steroidal Alkaloids Inhibit β-1,6-Glucan Biosynthesis in Fungal Cell Walls

2022 ◽  
Author(s):  
Karen Kubo ◽  
Kaori Itto-Nakama ◽  
Shinsuke Ohnuki ◽  
Yoko Yashiroda ◽  
Sheena C. Li ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Cell Walls ◽  
Therapeutic Agents ◽  
Antifungal Drugs ◽  
Steroidal Alkaloids ◽  
Fungal Cell ◽  
Content Type ◽  
Fungal Cell Walls

Non- Candida albicans Candida species (NCAC) are on the rise as a cause of mycosis. Many antifungal drugs are less effective against NCAC, limiting the available therapeutic agents.

scholarly journals Bdelloid rotifers use hundreds of horizontally acquired genes against fungal pathogens

2021 ◽  
Author(s):  
Reuben W Nowell ◽  
Timothy G Barraclough ◽  
Christopher G Wilson
Keyword(s):  
Fungal Pathogen ◽  
Cell Walls ◽  
Fungal Pathogens ◽  
Fungal Cell ◽  
Bdelloid Rotifers ◽  
Fungal Toxins ◽  
Foreign Genes ◽  
Fungal Cell Walls

Obligately asexual lineages are typically rare and short-lived. According to one hypothesis, they adapt too slowly to withstand relentlessly coevolving pathogens. Bdelloid rotifers seem to have avoided this fate, by enduring millions of years without males or sex. We investigated whether bdelloids' unusual capacity to acquire non-metazoan genes horizontally has enhanced their resistance to pathogens. We found that horizontally transferred genes are three times more likely than native genes to be upregulated in response to a natural fungal pathogen. This enrichment was twofold stronger than that elicited by a physical stressor (desiccation), and the genes showed little overlap. Among hundreds of upregulated non-metazoan genes were RNA ligases putatively involved in resisting fungal toxins and glucanases predicted to bind to fungal cell walls, acquired from bacteria. Our results provide evidence that bdelloids mitigate a predicted challenge of long-term asexuality in part through their ability to acquire and deploy so many foreign genes.

scholarly journals A secreted LysM effector protects fungal hyphae through chitin-dependent homodimer polymerization

2019 ◽  
Author(s):  
Andrea Sánchez-Vallet ◽  
Hui Tian ◽  
Luis Rodriguez-Moreno ◽  
Dirk-Jan Valkenburg ◽  
Raspudin Saleem-Batcha ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Walls ◽  
Fungal Pathogens ◽  
Cladosporium Fulvum ◽  
Zymoseptoria Tritici ◽  
Fungal Cell ◽  
Lysm Domain ◽  
Fungal Hyphae ◽  
Binding Groove ◽  
Fungal Cell Walls

ABSTRACTPlants trigger immune responses upon recognition of fungal cell wall chitin, followed by the release of various antimicrobials, including chitinase enzymes that hydrolyze chitin. In turn, many fungal pathogens secrete LysM effectors that prevent chitin recognition by the host through scavenging of chitin oligomers. We previously showed that intrachain LysM dimerization of the Cladosporium fulvum effector Ecp6 confers an ultrahigh-affinity binding groove that competitively sequesters chitin oligomers from host immune receptors. Additionally, particular LysM effectors are found to protect fungal hyphae against chitinase hydrolysis during host colonization. However, the molecular basis for the protection of fungal cell walls against hydrolysis remained unclear. Here, we determined a crystal structure of the single LysM domain-containing effector Mg1LysM of the wheat pathogen Zymoseptoria tritici and reveal that Mg1LysM is involved in the formation of two kinds of dimers; a chitin-dependent dimer as well as a chitin-independent homodimer. In this manner, Mg1LysM gains the capacity to form a supramolecular structure by chitin-induced oligomerization of chitin-independent Mg1LysM homodimers, a property that confers protection to fungal cell walls against host chitinases.

scholarly journals Trimming Surface Sugars Protects Histoplasma from Immune Attack

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Gordon D. Brown
Keyword(s):  
Cell Walls ◽  
Fungal Pathogens ◽  
Recent Article ◽  
Histoplasma Capsulatum ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Immune Recognition ◽  
Fungal Cell ◽  
Immune Attack ◽  
Fungal Cell Walls

ABSTRACT Dectin-1 is an essential innate immune receptor that recognizes β-glucans in fungal cell walls. Its importance is underscored by the mechanisms that fungal pathogens have evolved to avoid detection by this receptor. One such pathogen is Histoplasma capsulatum , and in a recent article in mBio , Rappleye’s group presented data showing that yeasts of this organism secrete a β-glucanase, Eng1, which acts to prune β-glucans that are exposed on the fungal cell surface [A. L. Garfoot et al., mBio 7(2):e01388-15, 2016, http://dx.doi.org/10.1128/mBio.01388-15 ]. The trimming of these sugars reduces immune recognition through Dectin-1 and subsequent inflammatory responses, enhancing the pathogenesis of H. capsulatum .

scholarly journals A Fungus-Inducible Pepper Carboxylesterase Exhibits Antifungal Activity by Decomposing the Outer Layer of Fungal Cell Walls

2018 ◽  
Vol 31 (5) ◽  
pp. 505-515 ◽  
Author(s):  
Hyo-Hyoun Seo ◽  
Ae Ran Park ◽  
Hyun-Hwa Lee ◽  
Sangkyu Park ◽  
Yun-Jeong Han ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Cell Walls ◽  
Fungal Pathogens ◽  
Mass Spectrometry Analysis ◽  
Gas Chromatography Mass Spectrometry ◽  
Protective Effects ◽  
Fungal Cell ◽  
Spectrometry Analysis ◽  
Hydrolysis Of ◽  
Fungal Cell Walls

Colletotrichum species are major fungal pathogens that cause devastating anthracnose diseases in many economically important crops. In this study, we observed the hydrolyzing activity of a fungus-inducible pepper carboxylesterase (PepEST) on cell walls of C. gloeosporioides, causing growth retardation of the fungus by blocking appressorium formation. To determine the cellular basis for the growth inhibition, we observed the localization of PepEST on the fungus and found the attachment of the protein on surfaces of conidia and germination tubes. Moreover, we examined the decomposition of cell-wall materials from the fungal surface after reaction with PepEST, which led to the identification of 1,2-dithiane-4,5-diol (DTD) by gas chromatography mass spectrometry analysis. Exogenous DTD treatment did not elicit expression of defense-related genes in the host plant but did trigger the necrosis of C. gloeosporioides. Furthermore, the DTD compound displayed protective effects on pepper fruits and plants against C. gloeosporioides and C. coccodes, respectively. In addition, DTD was also effective in preventing other diseases, such as rice blast, tomato late blight, and wheat leaf rust. Therefore, our results provide evidence that PepEST is involved in hydrolysis of the outmost layer of the fungal cell walls and that DTD has antifungal activity, suggesting an alternative strategy to control agronomically important phytopathogens.

Rapid determination of binding parameters of chitin binding domains using chitin-coated quartz crystal microbalance sensor chips

The Analyst ◽  
2018 ◽  
Vol 143 (21) ◽  
pp. 5255-5263 ◽  
Author(s):  
Stephan Vogt ◽  
Marco Kelkenberg ◽  
Tanja Nöll ◽  
Benedikt Steinhoff ◽  
Holger Schönherr ◽  
...  
Keyword(s):  
Cell Walls ◽  
Quartz Crystal ◽  
Fungal Infections ◽  
Rapid Determination ◽  
Binding Parameters ◽  
Fungal Cell ◽  
Binding Domains ◽  
Quartz Crystal Microbalance Sensor ◽  
Fungal Cell Walls

Chitin present in fungal cell walls has been considered as a diagnostic polymer for the detection of fungal infections.

scholarly journals Lactoferrin Is Broadly Active against Yeasts and Highly Synergistic with Amphotericin B

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Kenya E. Fernandes ◽  
Kerry Weeks ◽  
Dee A. Carter
Keyword(s):  
Amphotericin B ◽  
Galleria Mellonella ◽  
Comprehensive Evaluation ◽  
Yeast Species ◽  
Phenotypic Diversity ◽  
Antifungal Drugs ◽  
Fungal Cell ◽  
Content Type ◽  
Iron Saturation ◽  
Capsule Size

ABSTRACT Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens. While numerous studies report that LF is active against fungi, there are considerable differences in the level of antifungal activity and the capacity of LF to interact with other drugs. Here we undertook a comprehensive evaluation of the antifungal spectrum of activity of three defined sources of LF across 22 yeast and 24 mold species and assessed its interactions with six widely used antifungal drugs. LF was broadly and consistently active against all yeast species tested (MICs, 8 to 64 μg/ml), with the extent of activity being strongly affected by iron saturation. LF was synergistic with amphotericin B (AMB) against 19 out of 22 yeast species tested, and synergy was unaffected by iron saturation but was affected by the extent of LF digestion. LF-AMB combination therapy significantly prolonged the survival of Galleria mellonella wax moth larvae infected with Candida albicans or Cryptococcus neoformans and decreased the fungal burden 12- to 25-fold. Evidence that LF directly interacts with the fungal cell surface was seen via scanning electron microscopy, which showed pore formation, hyphal thinning, and major cell collapse in response to LF-AMB synergy. Important virulence mechanisms were disrupted by LF-AMB treatment, which significantly prevented biofilms in C. albicans and C. glabrata, inhibited hyphal development in C. albicans, and reduced cell and capsule size and phenotypic diversity in Cryptococcus. Our results demonstrate the potential of LF-AMB as an antifungal treatment that is broadly synergistic against important yeast pathogens, with the synergy being attributed to the presence of one or more LF peptides.

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