Conservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control

ABSTRACT Candida biofilms resist the effects of available antifungal therapies. Prior studies with Candida albicans biofilms show that an extracellular matrix mannan-glucan complex (MGCx) contributes to antifungal sequestration, leading to drug resistance. Here we implement biochemical, pharmacologi...

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Autores principales:	Eddie Dominguez, Robert Zarnowski, Hiram Sanchez, Antonio S. Covelli, William M. Westler, Parastoo Azadi, Jeniel Nett, Aaron P. Mitchell, David R. Andes
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	biofilm Candida non-albicans antifungal resistance extracellular matrix Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/172e5758db3c4bb5b3e4a404ffd91f0f
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spelling	oai:doaj.org-article:172e5758db3c4bb5b3e4a404ffd91f0f2021-11-15T15:53:26ZConservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control10.1128/mBio.00451-182150-7511https://doaj.org/article/172e5758db3c4bb5b3e4a404ffd91f0f2018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00451-18https://doaj.org/toc/2150-7511ABSTRACT Candida biofilms resist the effects of available antifungal therapies. Prior studies with Candida albicans biofilms show that an extracellular matrix mannan-glucan complex (MGCx) contributes to antifungal sequestration, leading to drug resistance. Here we implement biochemical, pharmacological, and genetic approaches to explore a similar mechanism of resistance for the three most common clinically encountered non-albicans Candida species (NAC). Our findings reveal that each Candida species biofilm synthesizes a mannan-glucan complex and that the antifungal-protective function of this complex is conserved. Structural similarities extended primarily to the polysaccharide backbone (α-1,6-mannan and β-1,6-glucan). Surprisingly, biochemical analysis uncovered stark differences in the branching side chains of the MGCx among the species. Consistent with the structural analysis, similarities in the genetic control of MGCx production for each Candida species also appeared limited to the synthesis of the polysaccharide backbone. Each species appears to employ a unique subset of modification enzymes for MGCx synthesis, likely accounting for the observed side chain diversity. Our results argue for the conservation of matrix function among Candida spp. While biogenesis is preserved at the level of the mannan-glucan complex backbone, divergence emerges for construction of branching side chains. Thus, the MGCx backbone represents an ideal drug target for effective pan-Candida species biofilm therapy. IMPORTANCE Candida species, the most common fungal pathogens, frequently grow as a biofilm. These adherent communities tolerate extremely high concentrations of antifungal agents, due in large part, to a protective extracellular matrix. The present studies define the structural, functional, and genetic similarities and differences in the biofilm matrix from the four most common Candida species. Each species synthesizes an extracellular mannan-glucan complex (MGCx) which contributes to sequestration of antifungal drug, shielding the fungus from this external assault. Synthesis of a common polysaccharide backbone appears conserved. However, subtle structural differences in the branching side chains likely rely upon unique modification enzymes, which are species specific. Our findings identify MGCx backbone synthesis as a potential pan-Candida biofilm therapeutic target.Eddie DominguezRobert ZarnowskiHiram SanchezAntonio S. CovelliWilliam M. WestlerParastoo AzadiJeniel NettAaron P. MitchellDavid R. AndesAmerican Society for MicrobiologyarticlebiofilmCandidanon-albicansantifungal resistanceextracellular matrixMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	biofilm Candida non-albicans antifungal resistance extracellular matrix Microbiology QR1-502
spellingShingle	biofilm Candida non-albicans antifungal resistance extracellular matrix Microbiology QR1-502 Eddie Dominguez Robert Zarnowski Hiram Sanchez Antonio S. Covelli William M. Westler Parastoo Azadi Jeniel Nett Aaron P. Mitchell David R. Andes Conservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control
description	ABSTRACT Candida biofilms resist the effects of available antifungal therapies. Prior studies with Candida albicans biofilms show that an extracellular matrix mannan-glucan complex (MGCx) contributes to antifungal sequestration, leading to drug resistance. Here we implement biochemical, pharmacological, and genetic approaches to explore a similar mechanism of resistance for the three most common clinically encountered non-albicans Candida species (NAC). Our findings reveal that each Candida species biofilm synthesizes a mannan-glucan complex and that the antifungal-protective function of this complex is conserved. Structural similarities extended primarily to the polysaccharide backbone (α-1,6-mannan and β-1,6-glucan). Surprisingly, biochemical analysis uncovered stark differences in the branching side chains of the MGCx among the species. Consistent with the structural analysis, similarities in the genetic control of MGCx production for each Candida species also appeared limited to the synthesis of the polysaccharide backbone. Each species appears to employ a unique subset of modification enzymes for MGCx synthesis, likely accounting for the observed side chain diversity. Our results argue for the conservation of matrix function among Candida spp. While biogenesis is preserved at the level of the mannan-glucan complex backbone, divergence emerges for construction of branching side chains. Thus, the MGCx backbone represents an ideal drug target for effective pan-Candida species biofilm therapy. IMPORTANCE Candida species, the most common fungal pathogens, frequently grow as a biofilm. These adherent communities tolerate extremely high concentrations of antifungal agents, due in large part, to a protective extracellular matrix. The present studies define the structural, functional, and genetic similarities and differences in the biofilm matrix from the four most common Candida species. Each species synthesizes an extracellular mannan-glucan complex (MGCx) which contributes to sequestration of antifungal drug, shielding the fungus from this external assault. Synthesis of a common polysaccharide backbone appears conserved. However, subtle structural differences in the branching side chains likely rely upon unique modification enzymes, which are species specific. Our findings identify MGCx backbone synthesis as a potential pan-Candida biofilm therapeutic target.
format	article
author	Eddie Dominguez Robert Zarnowski Hiram Sanchez Antonio S. Covelli William M. Westler Parastoo Azadi Jeniel Nett Aaron P. Mitchell David R. Andes
author_facet	Eddie Dominguez Robert Zarnowski Hiram Sanchez Antonio S. Covelli William M. Westler Parastoo Azadi Jeniel Nett Aaron P. Mitchell David R. Andes
author_sort	Eddie Dominguez
title	Conservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control
title_short	Conservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control
title_full	Conservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control
title_fullStr	Conservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control
title_full_unstemmed	Conservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control
title_sort	conservation and divergence in the <italic toggle="yes">candida</italic> species biofilm matrix mannan-glucan complex structure, function, and genetic control
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/172e5758db3c4bb5b3e4a404ffd91f0f
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Conservation and Divergence in the <italic toggle="yes">Candida</italic> Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control

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