Fungal biofilm resistance

Abstract

Fungal biofilm infections have become increasingly recognised as a significant clinical problem. One of the major reasons behind this is the impact that these have upon treatment, as antifungal therapy often fails and surgical intervention is required. This places a large financial burden on health care providers. This paper aims to illustrate the importance of fungal biofilms, particularly Candida albicans, and discusses some of the key fungal biofilm resistance mechanisms that include, extracellular matrix (ECM), efflux pump activity, persisters, cell density, overexpression of drug targets, stress responses, and the general physiology of the cell. The paper demonstrates the multifaceted nature of fungal biofilm resistance, which encompasses some of the newest data and ideas in the field.

Figure 1

Schematic overview of fungal biofilm resistance mechanisms. Generic overview of key biofilm resistance mechanisms associated with C. albicans, but which are likely to be common to other fungi. This figure illustrates the density and complexity of the C. albicans biofilm, with different morphotypes present surrounded by ECM. The arrows represent the different factors that drive antifungal resistance within the biofilm, including density, stress, persisters, ECM, efflux, overexpressed targets, and the general physiology of the biofilm. These have been placed according to their contribution to resistance, with those that have a greater effect closer to the middle and those with less impact at the edges.

Figure 2

Molecular mechanisms of fungal biofilm resistance. Antifungal drug resistance in fungal biofilms is both complex and multifactorial. The diagram illustrates the mechanisms of different class of antifungal agent action (azoles [AZL], polyenes [POL], and echinocandins [ECN]) and resistance: (a) the layer of ECM present in the biofilm shields the cells from antifungal agents by binding and reduced penetration; (b) the membrane transporter system ABC and MFS efflux pumps extrude antifungal molecules and reduce the intracellular concentration; (c) mutation in ERG, Cyp51, and FKS1 genes alters the drug target leading to cross-resistance; (d) antifungal pressure induces stress responses, such as the calcineurin signalling pathway, which is activated, and coping responses occur through upregulation of various signal transducers. On the right hand side, the table lists different resistance genes and their functions, and antifungal agents affected.