Pharmacological evaluation of synthetic galloyl catechin analogues with anti-staphylococcal properties

抗生素是有史以来最有益的药物之一，但它们的使用受到抗生素耐药性细菌的出现和传播的影响。对新的感染治疗方法的需求从未如此之大，但社会反应缓慢，我们现在面临的情况是，MRSA等超级细菌经常导致难以治疗，危及生命的感染，这些细菌在我们医院的定植越来越有可能导致取消大手术。这个问题是世界性的重要性，在美国，MRSA现在比艾滋病病毒杀死更多的病人。我们一直在研究逆转MRSA抗生素耐药性的方法，使其再次对甲氧西林和苯唑西林等廉价抗生素敏感。这些抗生素阻止细菌制造它们生存所需的刚性细胞壁; MRSA通过改变其制造细胞壁的方式来破坏这种行为。我们发现，日本绿色茶中一种名为表儿茶素没食子酸酯（epicatechin gallate，简称ECG）的成分会干扰MRSA破坏机制，并将细菌转化为甲氧西林敏感性。我们研究了ECg在MRSA中的主要靶点，并获得了强有力的证据表明它通过与MRSA膜结合而发挥其耐药性修饰作用。MRSA和其他葡萄球菌是危险的病原体，因为它们不仅对我们最好的抗生素有抗药性，而且还分泌一系列毒素，这些毒素会损害宿主，引起疾病症状，并绕过身体的免疫防御。这些蛋白质必须穿过细胞膜运输到细胞外才能损害患者：我们发现ECG可以阻止这种运输过程，有效地解除病原体的武装，并提高了它本身可用作治疗的可能性。不幸的是，心电图具有许多特性，可能会阻止其治疗用途-它在体内被分解为非活性化合物，其效力仅为中等-但我们已经设计了设计分子的方法，以提高其作为药物的吸引力。因此，我们建议通过合理的设计和化学合成的新型类似物，以提高心电图的潜力，并确定其性质在实验室和感染模型。我们希望这些研究将使我们能够将关键的设计特征融入到我们可以进入下一个开发阶段的新药候选中。

Antibiotics are among the most beneficial drugs ever introduced but their use is compromised by the emergence and spread of antibiotic resistant bacteria. The need for new treatments for infection has never been greater but society has been slow to respond and we are now facing a situation where superbugs such as MRSA frequently cause difficult-to-treat, life-threatening infections and where colonisation of our hospitals by these bacteria is increasingly likely to result in the cancellation of major surgery. The problem is of worldwide importance and, in the USA, MRSA now kills more patients than the AIDS virus. We have been researching ways to reverse antibiotic resistance in MRSA, making it again sensitive to inexpensive antibiotics such as methicillin and oxacillin. These antibiotics prevent bacteria from making the rigid cell wall that they need to survive; MRSA subverts this action by altering the way it makes its wall. We have found that a constituent of Japanese green tea called epicatechin gallate, or ECg, interferes with the MRSA-subverting machinery and converts the bacteria to methicillin sensitivity. We investigated the main target for ECg in MRSA and obtained strong evidence that it exerts its resistance modifying effect by binding to the MRSA membrane. MRSA and other staphylococci are dangerous pathogens because, not only are they resistant to our best antibiotics, they also excrete a range of toxins that can damage the host, cause symptoms of disease and circumvent the bodys immune defences. These proteins must be transported across the membrane and out of the cell in order to damage the patient: we have found that ECg prevents this transport process, effectively disarming the pathogen and raising the possibility that it could be used as a therapeutic in its own right. Unfortunately, ECg has a number of properties that could prevent its therapeutic use - it is broken down to inactive compounds in the body and its potency is only moderate - but we have designed ways to engineer the molecule to improve its attraction as a drug. We therefore propose to enhance the potential of ECg through rational design and chemical synthesis of novel analogues and to determine their properties in the laboratory and in models of infection. We hope that these studies will enable us to incorporate key design features into a new drug candidate that we can take forward to the next stage of development.