BubblEs for TArgeting and TReatment of biOfilm InfectioNs (BETATRON)

抗菌剂，俗称抗生素，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，使抗生素不再有效治疗感染。抗生素耐药性是一个全球性的问题，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，所以我们需要改进它们的使用方式。目前，可以杀死多种细菌的广谱抗生素通常被大剂量使用，以确保足够的抗生素到达感染部位的微生物手中。使用的剂量比我们在感染部位提供抗生素所需的剂量要高得多。这些抗生素会杀死许多生活在我们体内的有益的“常驻”细菌，而这些细菌会导致耐药性。如果我们能使用一种“个性化药物”的方法，在感染部位按治疗问题所需的剂量在当地注射抗生素，那就更好了。通过给予较低剂量的靶向治疗和避免正常定植细菌暴露于抗生素，我们的愿景是改善健康结果，减少耐药微生物的选择。我们的项目涉及使用微泡，类似于已经用于超声波扫描的微泡，以研究血液通过心脏的流动，目前正在测试用于治疗癌症。这些气泡是通过向静脉注射的方式提供的。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。这些气泡也可以用更高功率的超声波来破裂，这是另一种可能的杀菌方法。这些气泡很小，比细菌大不了多少，并将被分子覆盖，使气泡附着在特定细菌的表面。这就是所谓的“分子靶向”。通过将气泡与超声波结合在一起，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地方的有益细菌。抗生素经常失败，因为细菌创造了自己的局部环境--充满粘性化学物质的生物膜，这也降低了抗生素的杀伤力。我们的方法将利用超声脉冲破裂气泡时释放的能量来帮助药物深入到这种“生物膜”中，从而帮助更有效地杀灭细菌。除了让更多的抗生素进入生物膜外，这些载药气泡还将使我们能够输送新型药物，例如抗菌肽(AMP)。AMP在杀灭细菌方面非常有效，但许多AMP不能以通常的方式，通过滴注进入静脉治疗感染，因为它们往往在到达感染部位之前在血液中分解。我们可以通过将AMP装载到附着在气泡上的微小保护性胶囊中，并在需要的地方/时间释放它们来克服这个问题。最后，我们计划调查是否可以使用气泡和超声波从当地的生物膜环境中释放细菌。在这里，我们将利用破裂的气泡释放的机械能来分解生物膜。从生物膜中释放出的细菌被称为“浮游性”，对传统的抗生素治疗更敏感。综上所述，我们建议：1.开发新的靶向剂，将气泡与细菌结合，并开发新的载药货物，以杀灭细菌/破坏生物膜。看看气泡和超声波是否可以一起用来将药物输送到细菌生物膜中，并更有效地杀灭细菌。使用我们的方法提供目前不能用于治疗患者的药物，因为它们在血液中被分解。

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.