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

目前用于治疗细菌感染的抗生素依赖于杀死有害细菌或阻止它们繁殖。不幸的是，许多抗微生物药物对感染无效，因为细菌已经找到了抵抗曾经有效药物的方法。治疗细菌感染的另一种方法是使用抗粘附抑制剂，这种分子可以阻止致病细菌粘附在宿主组织上。大多数细菌必须附着在宿主身上才能引起感染，它们使用表面的粘性蛋白质（粘附素）来做到这一点。如果它们粘附的结合位点已经被其他粘性分子（称为抗粘附抑制剂）占据，它们就不能附着自己，在不引起感染的情况下被排出生物体。我们利用这一策略来设计这种粘性抗粘附抑制剂作为预防和治疗感染的新药。我们已经开始使用从细菌粘附素中提取的分子作为抗粘附抑制剂——当它们被用来“治疗”宿主细胞时，它们会粘附并防止致病菌引起感染。最近我们发现了一个叫做MAMs的粘附素家族，许多不同的细菌都用它来粘附宿主。这意味着基于这些黏附素的抗黏附抑制剂将有助于抵御粘附在相同部位的各种不同致病菌（类似于广谱抗生素）。我们想要确切地研究这些蛋白质是如何粘附在宿主细胞上的（即它们如何识别宿主表面），以及在细菌的背景下，这些分子如何改变宿主细胞，使其更容易受到感染。如果我们能够理解基于mam的分子是如何与宿主紧密结合的（这样它们就能更好地抵御病原体），同时又不会对细胞本身造成伤害，我们就能制造出可以替代抗生素的新药。优点是它们将在很长一段时间内有效，因为细菌不容易对抗粘连治疗产生抗药性。

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.