Drug induced tolerance mechanisms of the fungal pathogen Candida albicans

Echinocandin antibiotics inhibit the synthesis of the polysaccharide beta-glucan - an essential component of the fungal cell wall. We discovered that when exposed to echinocandins fungi make more chitin (another polysaccharide) to compensate for the damage to beta-glucan. We found that permanently antibiotic resistant mutant cells can be selected within the surviving high-chitin cell population that have adapted to echinocandin treatment. This surviving population has the potential to re-seed outbreak infections when antibiotic treatment is stopped. We have also discovered that high-chitin cell are less able to induce a damaging inflammatory response by the human immune system. In this project we will examine whether cells that survive echinocandin exposure are selected from those few cells that are naturally high in chitin or the cells that respond to drug exposure by making more chitin. We will investigate the compensatory mechanisms of key pathogenic Candida species induced by echinocandins, and how these changes affect cell wall structure and organisation, the immune response and patient survival after echinocandin treatment. We will use this information to explore how the compensatory mechanism might be compromised by adding inhibitory compounds leading to combination drug therapies that could make echinocandin antibiotics even more potent and broad spectrum.