Understanding the molecular survival strategies of Acinetobacter baumannii and developing strategies to disable them.

70多年前青霉素的发现，以及随后被世界各地的医疗系统采用，彻底改变了细菌感染的治疗方法。它标志着抗生素发现的黄金时代的开始，新的抗生素类别不断被发现，拯救了全球数百万人的生命。然而，在上个世纪末，发现的速度几乎停滞不前。这种缺乏发现的情况因对多种抗生素治疗表现出抗药性的细菌病原体的迅速出现和传播而变得更加复杂。世界卫生组织2018年的一份报告将鲍曼不动杆菌列为迫切需要新治疗策略的全球优先细菌名单的首位。鲍曼不动杆菌是一种机会性细菌，可以感染已经患病的人，导致各种危及生命的临床并发症和死亡。这造成了一个问题，特别是在鲍曼不动杆菌暴发最多的医院。在本世纪头十年之前，鲍曼不动杆菌感染相对较少，通常对大多数一线抗生素敏感。然而，这些感染的数量迅速增加，以至于这种病原体现在占全球重症监护病房(ICU)所有感染的20%。这些感染也变得越来越难以治疗，从患者身上分离出的鲍曼不动杆菌中有高达70%是多重耐药的。研究预防和治疗鲍曼不动杆菌感染的新战略现在是全球优先事项，以保持可持续获得有效治疗的机会。这些细菌用来阻止抗生素正常工作的一个关键策略是通过形成一个称为生物膜的细胞群落。通过在这些社区聚集在一起，细菌受到抗生素的保护，与细菌本身相比，在生物膜社区中杀死细菌所需的抗生素高达1000倍。鲍曼氏杆菌使用的另一种策略是，能够在扶手、桌子、病床和呼吸机等表面生存，一次可以在没有食物或水的情况下存活数月。这种生存能力使这种细菌在任何受感染的患者离开后仍能在医院存活很长时间，只有当病人接触到受感染的表面时才会重新融合。尽管这两种生存机制在这种病原体的传播和治疗困难中发挥了作用，但人们对控制这些生存策略的基因知之甚少。这项提议旨在通过描述调控鲍曼不动杆菌在干燥表面生存和形成生物膜的能力的关键基因和途径，建立在大量初步数据的基础上。我们还旨在确定将扰乱这些生存策略的新药，并可能成为防止后抗生素时代所需的下一代抗生素。鲍曼不动杆菌是创伤、手术或烧伤患者的一个特殊问题。事实上，众所周知，它会在烧伤重症监护室等专门伤口治疗中心引起疫情。我们还开发了一种高度创新的无脊椎动物实验，将用于研究伤口定植和生物膜形成。我们将通过开发含有我们下一代抗生素的新伤口敷料，探索给感染鲍曼不动杆菌的伤口输送药物的新方法。提案中概述的工作有可能迅速推进我们在基因水平上对这种病原体的理解，使我们对过去20年来出现这种病原体的关键生存机制有了新的见解。这一提议还有可能导致开发新的化合物，使这种病原体在患者的抗生素治疗中存活和/或在医院表面长时间存活的能力丧失。

The discovery of penicillin over 70 years ago, and its subsequent uptake by healthcare systems around the world, revolutionised the treatment of bacterial infections. It marked the beginning of a golden age in antibiotic discovery with new classes of antibiotics being routinely discovered, saving millions of lives globally. However, towards the end of the last century the rate of discovery slowed to a near standstill. This lack of discovery has been compounded by the rapid emergence and spread of bacterial pathogens that exhibit resistance to multiple antibiotic treatments. A 2018 report from the World Health Organisation placed Acinetobacter baumannii at the top of a global priority list of bacteria in urgent need of novel treatment strategies. A. baumannii is an opportunistic bacteria that can infect individuals who are already sick leading to a variety of life threatening clinical complications and death. This creates a problem particularly in hospitals where most A. baumannii outbreaks occur. Prior to the 2000s, A. baumannii infections were relatively infrequent and typically susceptible to most front line antibiotics. However, there has been a rapid increase in the number of these infections, such that this pathogen now accounts for 20% of all infections seen in Intensive Care Units (ICUs) worldwide. These infections are also becoming increasingly difficult to treat, with up to 70% of A. baumannii isolated from patients being multidrug resistant. Research into new strategies to prevent and treat A. baumannii infections is now a matter of global priority in order to maintain sustainable access to effective treatments. One key strategy that these bacteria use to stop antibiotics working properly is by forming a community of cells called a biofilm. By coming together in these communities, bacteria are protected from antibiotics, with up to 1,000 times more antibiotic being needed to kill bacteria in a biofilm community compared to bacteria on their own. Another strategy used by A. baumannii is the ability to survive on surfaces like handrails, desks, hospital beds and ventilators, without food or water for months at a time. This survival ability allows this bacteria to survive in hospitals long after any infected patients have left, only to remerge when a sick individual comes in contact with an infected surface. Despite the role that these two survival mechanisms play in the spread and difficulty in treating this pathogen, very little is known about the genes that control these survival strategies. This proposal aims to build on considerable preliminary data by characterising key genes and pathways that regulate the ability of A. baumannii to survive on dry surfaces and to form biofilms. We also aim to identify new drugs that will disrupt these survival stratagies and could potentially be the next generation of antibiotics needed to prevent a post-antibiotic era. A. baumannii is a particular problem for patients with wounds from trauma, surgery or burns. In fact, it has been known to cause outbreaks in specialist wound treatment centres such as Burn ICUs. We have also developed a highly innovative invertebrate assay that will be used to study wound colonisation and biofilm formation. We will explore new ways to deliver drugs to wounds infected with A. baumannii by developing new wound dressings that contain our next generation antibiotics. The work outlined in the proposal has the potential to rapidly advance our understanding of this pathogen at a genetic level, giving novel insights into the key survival mechanisms that have been central to its emergence over the last 20 years. This proposal also has the potential to lead to the development of novel compounds that disable the ability of this pathogen to survive antibiotic treatment in patients and/or survive on hospital surfaces for long periods of time.