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

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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.