Molecular and functional characterization of protein-lipid interactions at the bacterial host interface

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Currently available antibiotics for the treatment of bacterial infections rely on killing harmful bacteria or stopping them from multiplying. Unfortunately, many antimicrobials are becoming ineffective against infections because bacteria have come up with ways to resist drugs which once were effective. An alternative way of treating bacterial infections is the use of anti-adhesion inhibitors, molecules that stop disease-causing bacteria from sticking to host tissues. Most bacteria have to attach themselves to the host to cause infections and they use sticky proteins (adhesins) on their surface to do this. If the binding sites they stick to are already taken up by other sticky molecules (called anti-adhesion inhibitors), they cannot attach themselves and are flushed out of the organisms without causing infection. We use this strategy to design such sticky anti-adhesion inhibitors as new drugs to prevent and treat infections. We have started using molecules derived from bacterial adhesins as anti-adhesion inhibitors - when they are used to "treat" host cells, they stick and prevent pathogenic bacteria from causing infection. Recently we found a family of adhesins, called MAMs, which are used by many different bacteria to stick to the host. This means that anti-adhesion inhibitors based on these adhesins will be useful in fending off a wide range of different pathogenic bacteria (similar to broad-spectrum antibiotics) that would stick to the same sites. We want to study exactly how these proteins stick to the host cells (i.e. how can they recognize the host surface) and how, in the context of bacteria, these molecules can change the host cell so that it becomes more prone to infection. If we can understand how MAM-based molecules manage to bind to the host really tightly (so they are better at fending off pathogens) but without causing harm to the cells themselves, we will be able to make new drugs which can be used instead of antibiotics. The advantage will be that they will be effective for a long time to come, because bacteria cannot easily become resistant against anti-adhesion therapy.