Extending the utility and durability of antifungal agents via innovative treatment regimens that minimise drug resistance

一种名为假丝酵母菌的真菌生活在人体内，有时会导致人类致命的感染，通常是在遭受身体创伤或免疫力减弱的患者中。当检测到血流或其他正常无菌身体部位的念珠菌感染(侵袭性念珠菌病)时，使用抗真菌药物进行快速治疗可能是一种挽救生命的措施。不幸的是，有效药物的数量有限，假丝酵母菌对它们的抗药性越来越强。这一困境最近被世界卫生组织强调为一种日益受到关注的公共卫生危机。侵袭性念珠菌病是英国最常见的侵袭性真菌感染，估计每年有5000例。重症监护病房中的危重病人尤其脆弱，估计有30%-40%的所有感染发生在这种环境中。不幸的是，即使使用了抗真菌药物，高达50%的患者也无法存活。治疗选择有限，仅有四类抗真菌药物可供选择：氮唑类；棘球菌素类；多烯类；核苷类似物。保持这些药物的有效性对于确保我们在未来拥有可行的治疗方案来管理侵袭性念珠菌病至关重要。这就是这项研究的主要目的。有几种方法可以用来保存现有抗真菌药物的有效性。一是改变它们的使用方式，最好是减少使用频率或达到效果所需的药量。另一种是结合不同的药物类别(称为联合疗法)。最好的抗真菌用法改进将保持抗真菌活性，但减少耐药性的出现。为了实现这一点，我们需要彻底了解抗真菌耐药性(AFR)是如何发展的。AFR可以定义为真菌细胞在高浓度抗真菌药物存在下生长的能力。这种行为很容易在实验室中研究，因为真菌细胞可以非常快地(一夜之间)生长，我们有许多方法来观察它们对抗真菌药物的反应，例如显微镜和生长测试。在这个工作计划中，我们将连接利物浦、伦敦和埃克塞特的三个世界级研究中心，以发现防止真菌生长的新药和药物组合，并限制AFR。第一步将是测量五种不同的念珠菌在各种抗真菌药物和药物组合存在下的生长情况，包括即将上市的新抗真菌药物。最有效的药物治疗将继续进行，以研究它们在侵袭性念珠菌病小鼠模型中的有效性。通过了解假丝酵母菌在实验室环境下、小鼠和危重病人对真菌药物的适应方式，我们可以开发新的测试来早期识别AFR，当这种情况发生在感染期间。通过作为科学家和临床医生团队的工作，我们可以分享重要的知识，并根据当前的实践，开发更好的AFR测试。反过来，这将有助于临床医生在治疗过程中检测AFR，并修改患者的治疗以获得更好的结果。

A type of fungus called Candida, that lives on and in the human body, can sometimes cause fatal infections in humans, usually in patients who have suffered from a physical trauma or have weakened immunity. When a Candida infection of the bloodstream or other normally sterile body site (invasive candidiasis) is detected, rapid treatment with antifungal drugs can be a lifesaving measure. Unfortunately, there are a limited number of effective drugs, and Candida species are becoming more resistant to them. This dilemma has recently been highlighted by the World Health Organisation as a public health crisis of growing concern.Invasive candidiasis is the most common invasive fungal infection in the UK, with an estimated 5,000 cases each year. Critically ill patients in intensive care units are particularly vulnerable, with an estimated 30-40% of all infections occurring in this setting. Unfortunately, even with the use of antifungal drugs, up to 50% of patients will not survive. Treatment options are limited with just four antifungal drug classes available; azoles; echinocandins; polyenes; nucleoside analogues. Preserving the effectiveness of these drugs is vital for ensuring we have viable treatment options to manage invasive candidiasis in the future. This is the overarching aim of this study.There are several approaches that can be used to preserve the effectiveness of available antifungal drugs. One is to change the way in which they are used, preferably by reducing the frequency of use or the amount of drug needed to achieve an effect. Another is to combine different drug classes (called combination therapy). The best modifications of antifungal use will maintain antifungal activity but reduce the rate of emergence of drug resistance. To achieve this, we need a thorough understanding of how antifungal resistance (AFR) develops. AFR can be defined as the ability of fungal cells to grow in the presence of high concentrations of antifungal drug. This behaviour can be readily studied in the lab since fungal cells can be grown very quickly (overnight) and we have many methods for observing their responses to antifungal drugs, such as microscopy and growth tests.In this programme of work, we will connect three world class research centres in Liverpool, London and Exeter to discover new drugs and drug combinations that prevent fungal growth, and limit AFR. The first step will be to measure the growth of five different Candida species in the presence of various antifungal drugs and drug combinations, including new antifungal drugs that will soon come to market. The most effective drug treatments will then be progressed to study their effectiveness in a mouse model of invasive candidiasis. By learning about the way that Candida species adapt to fungal drugs in the laboratory setting, in mice and in critically ill patients, we can develop new tests to recognise AFR early when this happens during an infection. By working as a team of scientists and clinicians we can share important knowledge and, informed by current practices, develop better tests for AFR. In turn this will help clinicians to detect AFR as it emerges during treatment, and to modify patients' treatment for a better outcome.