Candida albicans Mycofilms Support Staphylococcus aureus Colonization and Enhances Miconazole Resistance in Dual-Species Interactions

Abstract

Polymicrobial inter-kingdom biofilm infections represent a clinical management conundrum. The presence of co-isolation of bacteria and fungi complicates the ability to routinely administer single antimicrobial regimens, and synergy between the microorganisms influences infection severity. We therefore investigated the nosocomial pathogens <i>Staphylococcus aureus</i> and <i>Candida albicans</i> with respect to antimicrobial intervention. We characterized the interaction using biofilm assays and evaluated the effect of miconazole treatment using <i>in vitro</i> and <i>in vivo</i> assays. Finally, we assessed the impact of biofilm extracellular matrix (ECM) on these interactions. Data indicated that the <i>C. albicans</i> mycofilms supported adhesion and colonization by <i>S. aureus</i> through close interactions with hyphal elements, significantly increasing <i>S. aureus</i> biofilm formation throughout biofilm maturation. Miconazole sensitivity was shown to be reduced in both mono- and dual-species biofilms compared to planktonic cells. Within a three-dimensional biofilm model sensitivity was also hindered. <i>Galleria mellonella</i> survival analysis showed both enhanced pathogenicity of the dual-species infection, which was concomitantly desensitized to miconazole treatment. Analysis of the ECM revealed the importance of extracellular DNA, which supported the adhesion of <i>S. aureus</i> and the development of the dual-species biofilm structures. Collectively, these data highlight the clinical importance of dual-species inter-kingdom biofilm infections, though also provides translational opportunities to manage them more effectively.