BubblEs for TArgeting and TReatment of biOfilm InfectioNs (BETATRON)

抗微生物药物，通常被称为抗生素，由于耐药性而变得不那么有效。抗生素耐药性是指细菌或其他微生物发生变化，使抗生素不再起治疗感染的作用。抗生素耐药性是一个全球性问题，由于抗生素的过度使用而变得更加严重。我们可以通过开发更好的抗生素以及改进我们使用现有抗生素的方式来对抗抗生素耐药性。患者将继续需要抗生素，特别是治疗严重感染，如败血症，所以我们需要改进抗生素的使用方式。目前，杀死多种细菌的“广谱”抗生素通常使用大剂量，以确保有足够的抗生素到达感染部位的微生物。如果我们能够在感染部位使用抗生素，那么所需的剂量要高得多。这些抗生素杀死了许多生活在我们体内有益的“常驻”细菌，从而产生耐药性。如果我们能使用一种“个性化医疗”方法，在感染部位按治疗问题所需的剂量给药，那就好得多了。通过提供低剂量的靶向治疗和避免正常定植细菌接触抗生素，我们的愿景是改善健康结果并减少耐药微生物的选择。我们的项目涉及使用类似于超声扫描中使用的微小气泡来研究心脏中的血液流动，目前正在测试用于治疗癌症。这些气泡通过注射进入静脉。我们建议开发气泡，这样它们就可以将抗生素直接输送到感染部位。气泡也可以用更高功率的超声波来破裂，这是另一种杀死细菌的可能方法。气泡很小，不比细菌大多少，并且会被分子包裹，使气泡能够粘附在特定细菌的表面。这就是所谓的“分子靶向”。通过将气泡与超声波相结合，在感染部位触发抗生素的释放，我们的目标是减少杀死细菌所需的抗生素数量，而不会杀死生活在身体其他部位的有益细菌。抗生素常常不起作用，因为细菌在自己的局部环境中产生了“生物膜”，充满了粘性的化学物质，这也降低了抗生素的杀伤作用。我们的方法将利用超声波脉冲击破气泡时释放的能量，帮助将药物深入到这种“生物膜”中，从而帮助更有效地杀死细菌。除了让更多的抗生素进入生物膜之外，这些装载药物的气泡将使我们能够输送新型药物，例如抗菌肽（AMPs）。抗菌肽在杀死细菌方面非常有效，但许多抗菌肽不能以通常的方式，即通过滴注进入静脉来治疗感染，因为它们在到达感染部位之前往往会在血液中被分解。我们可以通过将amp装载到附着在气泡上的微小保护胶囊中并在需要时释放它们来克服这个问题。最后，我们计划研究是否可以使用气泡和超声波将细菌从其局部生物膜环境中释放出来。在这里，我们将利用气泡破裂所释放的机械能来打破生物膜。从生物膜中释放出来的细菌被称为“浮游生物”，它们更容易受到传统抗生素治疗的影响。综上所述，我们建议：开发新的靶向剂，使气泡与细菌结合，开发新的载药货物，以杀死细菌/破坏生物膜。看看气泡和超声波是否可以一起使用，将药物输送到细菌生物膜中，从而更有效地杀死细菌。使用我们的方法来提供目前不能用于治疗病人的药物，因为它们在血液中会被分解。

Antimicrobials, commonly known as antibiotics, are becoming less effective because of resistance. Antibiotic resistance is when bacteria or other microbes change so that antibiotics no longer work to treat infections. Antibiotic resistance is a global problem that is being made worse by antibiotic overuse. We can combat antibiotic resistance by developing better antibiotics as well as improving the way we use existing ones. Patients will continue to need antibiotics, particularly to treat serious infections, like sepsis, so we need to improve how they are used. Right now, 'broad-spectrum' antibiotics, that kill a wide range of bacteria, are often given in high doses to ensure that enough antibiotic reaches the microbes at the site of infection. Much higher doses than would be needed if we could deliver antibiotics just at the site of infection are used. These antibiotics kill many of the beneficial 'resident' bacteria living in our bodies, which drives resistance. It would be much better if we could use a 'personalised medicine' approach where antibiotics are delivered locally, at the site of infection, at doses necessary to treat the problem. By giving lower doses of targeted treatment and avoiding exposure of the normal colonising bacteria to antibiotics, our vision is to improve health outcomes and reduce the selection of resistant microbes.Our project involves using tiny bubbles similar to those already used with ultrasound scanning to study the flow of blood through the heart and are currently being tested to treat cancers. These bubbles are given by injection into a vein. We propose to develop bubbles so that they can deliver antibiotics directly to a site of infection. The bubbles can also be burst using higher powered ultrasound, which is another possible way to kill bacteria. The bubbles are tiny, not much bigger than the bacteria, and will be coated with molecules that will allow the bubbles to stick to the surface of specific bacteria. This is known as 'molecular targeting'. By combining bubbles with ultrasound to trigger the release of antibiotics just at the site of infection, we aim to reduce the amount of antibiotics required to kill bacteria, without killing the helpful bacteria that live elsewhere in the body. Antibiotics often fail because the bacteria create their own local environment, the "biofilm", full of sticky chemicals, which also reduces the killing effects of antibiotics. Our approach will harness the energy released when an ultrasound pulse bursts bubbles to help drive drugs deep into this "biofilm" and hence help kill bacteria more effectively. In addition to getting more antibiotic into a biofilm, these drug-loaded bubbles will allow us to deliver new types of drugs, e.g. antimicrobial peptides (AMPs). AMPs are very effective at killing bacteria, but many cannot be given in the usual way, via a drip, into a vein to treat infections because they tend to be broken down in the blood before getting to the infection site. We can overcome this problem by loading the AMPs into tiny protective capsules attached to the bubbles and release them where/when they are required. Finally, we plan to investigate if bacteria can be released from their local biofilm environment using bubbles plus ultrasound. Here we will harness the mechanical energy released by bursting bubbles to break up the biofilm. The bacteria released from the biofilm are known as 'planktonic' and are more susceptible to conventional antibiotic treatments. In summary, we propose to:1. Develop new targeting agents to bind bubbles to bacteria and new drug-loaded cargoes to kill bacteria/ destroy biofilms.2. See if bubbles and ultrasound can be used together to deliver drugs into bacterial biofilms and kill bacteria more effectively.3. Use our approaches to deliver drugs that cannot currently be used to treat patients because they are broken down in the blood.