'Silent' antibiotic resistance genes: an overlooked issue of considerable importance in antibacterial chemotherapy?

“沉默的”抗生素抗性基因：抗菌化疗中一个被忽视但相当重要的问题？

• 批准号: MR/M017710/1
• 负责人: Alex O'Neill
• 金额: $ 31.83万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM017710%2F1
• 关键词: Silent; antibiotic; resistance; genes; overlooked

Antibiotics enable the treatment and cure of life-threatening bacterial infections, and represent one of the great successes of modern medicine. Unfortunately, the utility of these agents is being progressively eroded as bacteria evolve to resist their effects, and antibiotic resistance is now considered one of the three greatest threats to human health. A key aspect of dealing with antibiotic resistance effectively in medical practice is strategic intelligence. Being in possession of up to date information about the proportion of bacterial strains in a given location that are resistant to particular antibiotics allows doctors to decide which would be the best antibiotics to use routinely to treat bacterial infection, and to avoid those which are probably not going to work because resistance is so commonplace. In the case of a life-threatening bacterial infection, knowing precisely which antibiotics the specific bacterium present in the patient is resistant or susceptible to enables the doctor to select the best antibiotic treatment to cure the patient.This project is focussed on investigating a phenomenon that may be seriously undermining our strategic intelligence regarding antibiotic resistance. Recent work in the applicant's laboratory has established that some bacteria that are sensitive to antibiotics nonetheless carry genes that are normally associated with antibiotic resistance, but that these genes have become switched off ('silenced'). This phenomenon, which we have termed 'silencing of antibiotic resistance by mutation' (SARM) is of considerable concern, as bacteria with SARM would appear susceptible to an antibiotic when tested, but could then very quickly and easily become resistant to the antibiotic during treatment in a patient. Currently, we do not know how widespread SARM is amongst bacteria that cause disease, nor do we understand properly how SARM occurs. The present proposal aims to investigate both of these issues in the so-called 'superbug', Staphylococcus aureus.To establish how common SARM is, a large collection of 1500 S. aureus isolates recovered from patients around the world will be tested. Each strain will undergo DNA sequencing of its genome to establish its complete genetic make-up, which will allow for the identification of genes that are known to be associated with antibiotic resistance. In addition, the susceptibility of each isolate to a wide range of commonly used antibiotics will be established to determine if the bacterium displays resistance to all the drugs that it has the genetic potential to display resistance to. Strains that carry antibiotic resistance genes, but do not exhibit resistance to the corresponding antibiotics, represent potential SARM strains. These strains will be studied in detail to establish how easily they can switch their 'silenced' resistance genes back on, and to understand the mechanism(s) by which SARM works.

抗生素能够治疗和治愈危及生命的细菌感染，是现代医学的伟大成就之一。不幸的是，随着细菌进化以抵抗其作用，这些药物的效用正在逐渐受到侵蚀，抗生素耐药性现在被认为是人类健康的三大威胁之一。在医疗实践中有效应对抗生素耐药性的一个关键方面是战略情报。拥有关于特定位置中对特定抗生素具有耐药性的细菌菌株比例的最新信息，使医生能够决定哪种抗生素是常规治疗细菌感染的最佳抗生素，并避免那些可能不起作用的抗生素，因为耐药性是如此普遍。在危及生命的细菌感染的情况下，准确了解患者体内存在的特定细菌对哪些抗生素具有耐药性或敏感性，使医生能够选择最佳的抗生素治疗方法来治愈患者。该项目的重点是调查一种可能严重破坏我们关于抗生素耐药性的战略情报的现象。申请人实验室的最近工作已经确定，一些对抗生素敏感的细菌仍然携带通常与抗生素抗性相关的基因，但是这些基因已经被关闭（“沉默”）。这种现象，我们称之为“突变沉默抗生素耐药性”（SARM）是相当令人担忧的，因为SARM细菌在测试时会对抗生素敏感，但在患者治疗期间可能很快容易对抗生素产生耐药性。目前，我们不知道SARM在致病细菌中的分布有多广，也不知道SARM是如何发生的。目前的建议旨在调查这两个问题，在所谓的'超级细菌'，金黄色葡萄球菌。将对从世界各地患者中回收的金黄色葡萄球菌分离株进行测试。每种菌株将对其基因组进行DNA测序，以确定其完整的遗传组成，这将允许识别已知与抗生素耐药性相关的基因。此外，将确定每种分离株对广泛的常用抗生素的敏感性，以确定细菌是否对所有具有遗传潜力的药物显示耐药性。携带抗生素抗性基因但不表现出对相应抗生素的抗性的菌株代表潜在的SARM菌株。这些菌株将被详细研究，以确定它们如何容易地将其“沉默”的抗性基因重新打开，并了解SARM的工作机制。

项目成果

Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure.

突变引起的抗生素耐药性短暂沉默是意外治疗失败的一个重要潜在来源。

• DOI: 10.17863/cam.45931
• 发表时间: 2019
• 作者: Kime L

Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure

• DOI: 10.1128/mbio.01755-19
• 发表时间: 2019-09-01
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Kime, Louise;Randall, Christopher P.;O'Neill, Alex J.
• 通讯作者: O'Neill, Alex J.