Abstract
ABSTRACTCandida 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.
Highlights
Candida biofilms resist the effects of available antifungal therapies
The yield of adherent cells was approximately fivefold lower for C. parapsilosis and C. glabrata than that measured for either C. albicans or C. tropicalis
Basic architecture in this model recapitulated the biofilm characteristics observed in vitro: filamentous cells were present in C. albicans, C. parapsilosis, and C. tropicalis biofilms, and extracellular matrix material was abundant
Summary
Prior studies with Candida albicans biofilms show that an extracellular matrix mannan-glucan complex (MGCx) contributes to antifungal sequestration, leading to drug resistance. Our findings reveal that each Candida species biofilm synthesizes a mannan-glucan complex and that the antifungal-protective function of this complex is conserved. Consistent with the structural analysis, similarities in the genetic control of MGCx production for each Candida species appeared limited to the synthesis of the polysaccharide backbone. The present studies define the structural, functional, and genetic similarities and differences in the biofilm matrix from the four most common Candida species. We present evidence of a conserved matrix mannan and glucan complex backbone (MGCx) which contributes to profound drug resistance exhibited by the four most prevalent Candida species. We show that select matrix synthesis C. albicans orthologs play similar roles across Candida species to synthesize a common polysaccharide backbone. Our findings argue that broad-spectrum Candida biofilm drug discovery should target the level of MGCx backbone synthesis as opposed to side chain synthesis
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