Article

Chitin synthesis and fungal pathogenesis. Curr Opin Microbiol

Aberdeen Fungal Group, School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK.
Current opinion in microbiology (Impact Factor: 5.9). 08/2010; 13(4):416-23. DOI: 10.1016/j.mib.2010.05.002
Source: PubMed

ABSTRACT

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. This review summarises latest advances in the analysis of chitin synthesis regulation in the context of fungal pathogenesis.

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Available from: Megan Denise Lenardon, Aug 13, 2015
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    • "The earliest inhibitors of chitin synthase are the naturally occurring polyoxins and nikkomycins (Fig. 1), which possess some of structural features of the natural substrate UDP-GlcNAc. They are the most potent chitin synthase inhibitors [12] [13]. However, despite excellent in vitro results , clinical utility of these inhibitors is compromised by their metabolic instability and poor cellular uptake, resulting in a decrease in efficacy. "
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    ABSTRACT: A series of novel phosphoramidate derivatives of coumarin have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their chitin synthase inhibition activity and antimicrobial activity in vitro. The bioactive assay manifested that most of the target compounds exhibited good efficacy against CHS and a variety of clinically important fungal pathogens. In particular, compound 7t with IC50 of 0.08 mM against CHS displayed stronger efficiency than the reference Polyoxin B with IC50 of 0.16 mM. In addition, the apparent Ki values of compound 7t was 0.096 mM while the Km of Chitin synthase prepared from Candida tropicalis was 3.86 mM for UDP-Nacetylglucosamine, and the result of the Ki showed that the compounds was a non-competitive inhibitor of the CHS. As far as the antifungal activity is concerned, compounds 7o, 7r and 7t were highly active against Aspergillus flavus with MIC values in the range of 1 μg/mL to 2 μg/Ml while the results of antibacterial screening showed that these compounds have negligible actions to the tested bacteria. These results indicated that the design of these compounds as antifungal agents was rational.
    Full-text · Article · Nov 2015 · European Journal of Medicinal Chemistry
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    • "Tofurthertestthehypothesisofamembraneactivecompound, theactivityagainsttheC.albicanscellmembranewasinvestigated usingachitinsynthaseinhibitor.Chitinisasimplepolysaccharide foundinthecellwallsoffungithatprovidescellstructureand rigidity(Lenardonetal.,2010).Itwasarguedthatifthecell membranewasthetargetofCHD-FA,thenbyweakeningthecell byinhibitingitschitinproductionwouldincreasetheexposure ofthecellmembranetotheagentandwouldincreaseCHD-FA sensitivity(Sherryetal.,2012).HereitwasdemonstratedthatC. albicanscellswerehyper-susceptibletoCHD-FAinthepresence ofachitinsynthaseinhibitor,afindingthatwasalsoobservedin voriconazoletreatedbiofilms(Kanekoetal.,2010).Collectively, thesedatasuggestthatCHD-FAactsthroughdisruptiontothe cellmembrane.Itisthereforefeasibletosuggestthatthisagent mayhavebroad-spectrumantimicrobialactivityagainstavariety offungiandbacteria.Indeed,thiswasthecasewhenCHD-FA wasshowntopossessantibacterialactivitytowardarangeoforal bacterialbiofilms,includinganinvitrofour-speciesperiodontal biofilmmodel(Sherryetal.,2013). "
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    ABSTRACT: Fungal infections have dramatically increased in the last decades in parallel with an increase of populations with impaired immunity, resulting from medical conditions such as cancer, transplantation, or other chronic diseases. Such opportunistic infections result from a complex relationship between fungi and host, and can range from self-limiting to chronic or life-threatening infections. Modern medicine, characterized by a wide use of biomedical devices, offers new niches for fungi to colonize and form biofilm communities. The capability of fungi to form biofilms is well documented and associated with increased drug tolerance and resistance. In addition, biofilm formation facilitates persistence in the host promoting a persistent inflammatory condition. With a limited availability of antifungals within our arsenal, new therapeutic approaches able to address both host and pathogenic factors that promote fungal disease progression, i.e., chronic inflammation and biofilm formation, could represent an advantage in the clinical setting. In this paper we discuss the antifungal properties of myriocin, fulvic acid, and acetylcholine in light of their already known anti-inflammatory activity and as candidate dual action therapeutics to treat opportunistic fungal infections.
    Full-text · Article · Oct 2015 · Frontiers in Microbiology
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    • "Importantly, chitin is not found in human cells and therefore represents an attractive target for antifungal therapy. In Candida albicans, the most common serious fungal pathogen of humans, chitin is synthesized by a family of four isoenzymes which fall into three different classes of chitin synthase enzymes, Chs1 (class II), Chs3 (class IV), Chs2 and Chs8 (class I) (reviewed in Lenardon et al. (2010b)). Together, these enzymes deposit chitin at sites of growth, which includes the polarized tips of buds and hyphae, and sites of septation. "
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    ABSTRACT: 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. albicans class I chitin synthases promote cell integrity during early polarized growth in yeast and hyphal cells. This was supported by live cell imaging of YFP-tagged versions of the class I chitin synthases which revealed that Chs2-YFP was localized at sites of polarized growth. Furthermore, a unique and dynamic pattern of localization of the class I enzymes at septa of yeast and hyphae was revealed. Phosphorylation of Chs2 on the serine at position 222 was shown to regulate the amount of Chs2 that is localized to sites of polarized growth and septation. Independently from this post-translational modification, specific cell wall stresses were also shown to regulate the amount of Chs2 that localizes to specific sites in cells, and this was linked to the ability of the class I enzymes to reinforce cell wall integrity during early polarized growth in the presence of these stresses. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Fungal Genetics and Biology
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