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

了解鲍曼不动杆菌的分子生存策略并制定使其失效的策略。

• 批准号: BB/V007823/1
• 负责人: Ronan McCarthy
• 金额: $ 57.51万
• 依托单位: Brunel University London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV007823%2F1
• 关键词: Understanding; molecular; survival; strategies; Acinetobacter

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.

青霉素在70多年前被发现，并随后被世界各地的卫生保健系统采用，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，新种类的抗生素被常规发现，拯救了全球数百万人的生命。然而，到上世纪末，发现的速度放缓到几乎停滞不前。由于对多种抗生素治疗表现出耐药性的细菌病原体的迅速出现和传播，这种缺乏发现的情况更加严重。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清单的首位。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，特别是在大多数鲍曼不动杆菌爆发的医院。在2000年代之前，鲍曼不动杆菌感染相对罕见，并且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，这种病原体现在占全世界重症监护病房（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高达70%具有多药耐药性。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，以便保持持续获得有效治疗。这些细菌用来阻止抗生素正常工作的一个关键策略是形成一个被称为生物膜的细胞群落。通过聚集在这些群落中，细菌可以免受抗生素的侵害，杀死生物膜群落中的细菌所需的抗生素是杀死细菌本身所需抗生素的1000倍。鲍曼不动杆菌采用的另一种策略是，在没有食物和水的情况下，能够在扶手、桌子、医院病床和呼吸机等表面生存数月。这种生存能力使这种细菌在任何受感染的病人离开医院后很长时间内仍能存活，只有当病人接触到受感染的表面时才会重新出现。尽管这两种生存机制在这种病原体的传播和治疗中发挥了作用，但人们对控制这些生存策略的基因知之甚少。该提案旨在通过描述调节鲍曼不动杆菌在干燥表面存活和形成生物膜的能力的关键基因和途径，建立相当多的初步数据。我们的目标还包括找到能够破坏这些生存策略的新药，并有可能成为防止后抗生素时代到来所需的下一代抗生素。鲍曼不动杆菌对创伤、手术或烧伤的病人来说是一个特别的问题。事实上，已知它会在烧伤重症监护室等专科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试验，将用于研究伤口定植和生物膜形成。我们将通过开发含有下一代抗生素的新型伤口敷料，探索将药物输送到感染鲍曼不动杆菌的伤口的新方法。提案中概述的工作有可能在遗传水平上迅速推进我们对这种病原体的理解，为过去20年来一直是其出现的核心的关键生存机制提供新的见解。这一建议也有可能导致新型化合物的发展，这些化合物可以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。

项目成果

Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

通过破坏胞质外蛋白折叠来打破抗菌药物耐药性

• DOI: 10.7554/elife.59046
• 发表时间: 2022
• 期刊: eLife
• 影响因子: 7.7
• 作者: Furniss R

A high-efficiency scar-free genome-editing toolkit for Acinetobacter baumannii.

• DOI: 10.1093/jac/dkac328
• 发表时间: 2022-11-28
• 期刊: The Journal of antimicrobial chemotherapy

Disrupting iron homeostasis can potentiate colistin activity and overcome colistin resistance mechanisms in Gram-Negative Bacteria.

• DOI: 10.1038/s42003-023-05302-2
• 发表时间: 2023-09-13
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Gadar, Kavita;de Dios, Ruben;Kaderabkova, Nikol;Prescott, Thomas A. K.;Mavridou, Despoina A. I.;McCarthy, Ronan R.
• 通讯作者: McCarthy, Ronan R.

Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding.

• DOI: 10.7554/elife.57974
• 发表时间: 2022-01-13
• 期刊: eLife
• 影响因子: 7.7
• 作者: Furniss RCD;Kaderabkova N;Barker D;Bernal P;Maslova E;Antwi AAA;McNeil HE;Pugh HL;Dortet L;Blair JMA;Larrouy-Maumus G;McCarthy RR;Gonzalez D;Mavridou DAI
• 通讯作者: Mavridou DAI

Enrichment of native plastic-associated biofilm communities to enhance polyester degrading activity

• DOI: 10.1111/1462-2920.16466
• 发表时间: 2023-07-28
• 期刊: ENVIRONMENTAL MICROBIOLOGY
• 影响因子: 5.1
• 作者: Howard, Sophie A. A.;Carr, Clodagh M. M.;McCarthy, Ronan R. R.
• 通讯作者: McCarthy, Ronan R. R.