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

抗生素是有史以来引入的最有益的药物之一，但抗生素耐药性细菌的出现和传播影响了它们的使用。对治疗感染的新方法的需求从未如此强烈，但社会反应迟缓，我们现在面临的情况是，像MRSA这样的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大手术的取消。这个问题具有世界范围的重要性，在美国，MRSA现在杀死的病人比艾滋病病毒还多。我们一直在研究如何逆转MRSA的抗生素耐药性，使其对甲氧西林和苯氧西林等廉价抗生素再次敏感。这些抗生素阻止细菌产生它们生存所需的坚硬细胞壁；MRSA通过改变其壁的方式颠覆了这一作用。我们发现日本绿茶中一种叫做表儿茶素没食子酸酯（ECg）的成分会干扰mrsa的破坏机制，并将细菌转化为对甲氧西林敏感。我们研究了ECg在MRSA中的主要靶点，并获得了强有力的证据，证明它通过与MRSA膜结合来发挥其耐药修饰作用。耐甲氧西林金黄色葡萄球菌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，而且还会分泌一系列毒素，这些毒素会损害宿主，引起疾病症状，并绕过人体的免疫防御。为了伤害病人，这些蛋白质必须通过细胞膜运输到细胞外：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，并提高了它本身可以作为治疗药物的可能性。不幸的是，心电图的一些特性可能会阻碍它的治疗用途——它在体内被分解成无活性的化合物，而且它的效力只有中等水平——但我们已经设计了一些方法来设计这种分子，以提高它作为药物的吸引力。因此，我们建议通过合理设计和化学合成新的类似物来增强ECg的潜力，并在实验室和感染模型中确定它们的特性。我们希望这些研究将使我们能够将关键设计特征纳入新的候选药物，我们可以将其推进到下一个开发阶段。

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.