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-真菌细胞壁的重要组成部分。我们发现，当暴露于棘白菌素时，真菌会产生更多的几丁质（另一种多糖）来弥补β-葡聚糖的损伤。我们发现，可以在存活的高几丁质细胞群中选择永久抗生素抗性突变细胞，这些细胞已经适应了棘白菌素治疗。当抗生素治疗停止时，这些幸存的人群有可能重新引发爆发感染。我们还发现，高几丁质细胞不太能够通过人类免疫系统诱导破坏性炎症反应。在这个项目中，我们将研究棘白菌素暴露后存活的细胞是否是从那些天然几丁质含量高的少数细胞中选择的，或者是通过制造更多几丁质对药物暴露做出反应的细胞。我们将研究由棘白菌素诱导的关键致病性念珠菌的代偿机制，以及这些变化如何影响细胞壁结构和组织，棘白菌素治疗后的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损害补偿机制，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.