Drug induced tolerance mechanisms of the fungal pathogen Candida albicans

棘白菌素抗生素抑制多糖β -葡聚糖的合成，葡聚糖是真菌细胞壁的重要成分。我们发现，当接触棘白菌素时，真菌会产生更多的几丁质（另一种多糖）来补偿β -葡聚糖的损害。我们发现永久耐抗生素突变细胞可以在适应棘白菌素治疗的存活的高几丁质细胞群中选择。当停止抗生素治疗时，这些幸存的人群有可能重新播下爆发感染的种子。我们还发现，高几丁质细胞不太能够引起人体免疫系统的破坏性炎症反应。在这个项目中，我们将研究在棘白菌素暴露下存活下来的细胞是从那些少数天然富含几丁质的细胞中选择出来的，还是从那些对药物暴露产生更多几丁质的细胞中选择出来的。我们将研究棘白菌素诱导的关键致病性念珠菌种类的代偿机制，以及这些变化如何影响棘白菌素治疗后细胞壁结构和组织、免疫反应和患者生存。我们将利用这些信息来探索如何通过添加抑制性化合物来破坏代偿机制，从而导致联合药物治疗，从而使棘白菌素抗生素更加有效和广谱。

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.