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

细菌宿主界面蛋白质-脂质相互作用的分子和功能表征

• 批准号: BB/L007916/1
• 负责人: Andrew Lovering
• 金额: $ 48.89万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL007916%2F1
• 关键词: Molecular; functional; characterization; protein; lipid

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.

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，许多抗微生物剂对感染变得无效，因为细菌已经想出了抵抗曾经有效的药物的方法。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（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，它们就不能附着在生物体上，并在不引起感染的情况下被冲出生物体。我们使用这种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。我们已经开始使用来自细菌粘附素的分子作为抗粘附抑制剂-当它们被用来“治疗”宿主细胞时，它们会粘附并防止病原菌引起感染。最近，我们发现了一个名为MAMs的粘附素家族，许多不同的细菌都使用它来粘附宿主。这意味着基于这些粘附素的抗粘附抑制剂将有助于抵御各种不同的病原菌（类似于广谱抗生素），这些病原菌会粘附在相同的部位。我们想确切地研究这些蛋白质如何粘附在宿主细胞上（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，使其变得更容易感染。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（因此它们更善于抵御病原体），但不会对细胞本身造成伤害，我们将能够制造出可替代抗生素的新药。优点是它们将在很长一段时间内有效，因为细菌不易对抗粘连治疗产生耐药性。

项目成果

There's More to Science than Research: A Team-Based Role Game to Develop School Students' Understanding of Science Careers in Pharmaceutical Quality Control.

科学不仅仅是研究：基于团队的角色游戏，培养学生对药品质量控制中科学职业的理解。

• DOI: 10.1128/jmbe.v16i2.917
• 发表时间: 2015
• 期刊: Journal of microbiology & biology education
• 影响因子: 1.9
• 作者: Collins R

Displacement of Pathogens by an Engineered Bacterium Is a Multifactorial Process That Depends on Attachment Competition and Interspecific Antagonism.

• DOI: 10.1128/iai.00020-16
• 发表时间: 2016-06
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Al-Saedi F;Stones DH;Vaz DP;Krachler AM
• 通讯作者: Krachler AM

Structural and regulatory mutations in Vibrio parahaemolyticus type III secretion systems display variable effects on virulence.

III型弧菌溶血性纤维溶血系统中的结构和调节突变对毒力显示出可变的影响。

• DOI: 10.1111/1574-6968.12619
• 发表时间: 2014-12
• 期刊: FEMS microbiology letters
• 影响因子: 2.1
• 作者: Calder T;de Souza Santos M;Attah V;Klimko J;Fernandez J;Salomon D;Krachler AM;Orth K
• 通讯作者: Orth K

A commensal adhesin enhances E. coli retention by mucin, while mucin desulfation by mucin-foraging bacteria enhances its transmigration through the mucus barrier

• DOI: 10.1101/126672
• 发表时间: 2017-04
• 期刊: bioRxiv
• 作者: Fitua Al-Saedi;D. Vaz;D. Stones;A. Krachler

Targeting bacterial adherence inhibits multidrug-resistant Pseudomonas aeruginosa infection following burn injury.

• DOI: 10.1038/srep39341
• 发表时间: 2016-12-20
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Huebinger RM;Stones DH;de Souza Santos M;Carlson DL;Song J;Vaz DP;Keen E;Wolf SE;Orth K;Krachler AM
• 通讯作者: Krachler AM