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

通过创新治疗方案最大限度地减少耐药性，延长抗真菌药物的效用和持久性

• 批准号: MR/Y002164/1
• 负责人: Elaine Bignell
• 金额: $ 408.84万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY002164%2F1
• 关键词: Extending; utility; durability; antifungal; agents

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.

一种名为念珠菌的真菌生活在人体表面和体内，有时会引起人类致命的感染，通常是在遭受身体创伤或免疫力下降的患者中。当检测到血液或其他通常无菌的身体部位出现念珠菌感染（侵袭性念珠菌病）时，使用抗真菌药物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，并且念珠菌对它们的抵抗力越来越强。这种困境最近被世界卫生组织强调为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，每年估计有 5,000 例病例。重症监护病房的重症患者特别容易受到伤害，估计所有感染的 30-40% 发生在重症监护室。不幸的是，即使使用抗真菌药物，仍有高达 50% 的患者无法生存。治疗选择有限，只有四种抗真菌药物可供选择；唑类；棘白菌素；多烯；核苷类似物。保持这些药物的有效性对于确保我们未来有可行的治疗方案来控制侵袭性念珠菌病至关重要。这是本研究的总体目标。有多种方法可用于保持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物量。另一种方法是结合不同的药物类别（称为联合疗法）。抗真菌药物使用的最佳修改将保持抗真菌活性，但降低耐药性的出现率。为了实现这一目标，我们需要彻底了解抗真菌耐药性（AFR）是如何产生的。 AFR可定义为真菌细胞在高浓度抗真菌药物存在下生长的能力。这种行为可以很容易地在实验室中进行研究，因为真菌细胞可以非常快速地生长（过夜），并且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，我们将连接三个利物浦、伦敦和埃克塞特的世界一流研究中心致力于发现预防真菌生长和限制 AFR 的新药和药物组合。第一步是测量五种不同念珠菌在各种抗真菌药物和药物组合（包括即将上市的新抗真菌药物）存在下的生长情况。然后将开发最有效的药物治疗，以研究其在侵袭性念珠菌病小鼠模型中的有效性。通过了解念珠菌在实验室环境、小鼠和危重患者中适应真菌药物的方式，我们可以开发新的测试，以便在感染期间发生 AFR 时及早识别 AFR。通过作为一个由科学家和临床医生组成的团队，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检测治疗过程中出现的 AFR，并调整患者的治疗以获得更好的结果。