Joint Transcriptional Control of Virulence and Resistance to Antibiotic and Environmental Stress in Acinetobacter baumannii.
Joint Transcriptional Control of Virulence and Resistance to Antibiotic and Environmental Stress in Acinetobacter baumannii.
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DOI：
10.1128/mbio.01660-15
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发表时间：
2015-11-10
期刊：
影响因子：
6.4
通讯作者：
Shuman HA
中科院分区：
文献类型：
--
作者：
Gebhardt MJ;Gallagher LA;Jacobson RK;Usacheva EA;Peterson LR;Zurawski DV;Shuman HA
越来越多的耐药细菌病原体的出现对人类健康和整个卫生保健系统构成严重威胁。许多目前流行的鲍曼不动杆菌菌株对多种抗生素表现出耐药性。对抗鲍曼不动杆菌的一个关键限制是我们对鲍曼不动杆菌发病机制的分子机制缺乏了解。为了鉴定当代多重耐药鲍曼不动杆菌分离株的潜在毒力决定因素，我们使用了菌株AB 5075的转座子插入测序（TnSeq）。分析了250，000个鲍曼不动杆菌转座子突变体的集合在大蜡螟幼虫（一种基于昆虫的感染模型）内的生长。筛选鉴定了300个基因，这些基因是鲍曼不动杆菌在大蜡螟幼虫体内生存和/或生长所特异性需要的。这些基因包括已知的、确定的毒力因子和几个新的基因。在这些转录因子中，有超过30种转录因子是大蜡螟生长所必需的。还发现转录因子的一个子集是对抗生素和环境应激的抗性所必需的。因此，这项工作建立了鲍曼不动杆菌毒力与抗生素耐药性和环境应激之间的新联系。鲍曼不动杆菌正迅速成为一种重要的人类病原体，主要是因为对消毒剂和抗生素的耐药性，导致脆弱宿主的致命感染。尽管多重耐药鲍曼不动杆菌菌株感染的流行率越来越高，但人们对鲍曼不动杆菌抵抗环境应激的分子机制（即，抗生素和消毒剂），而且还知道这些病原体如何在受感染的宿主体内存活以引起疾病。我们采用了大规模的遗传筛选来鉴定鲍曼不动杆菌在昆虫疾病模型中生存和生长所需的基因。虽然我们确定了鲍曼不动杆菌所携带的许多已知毒力因子，但我们还发现了许多新的基因，这些基因可能在鲍曼不动杆菌暴露于抗生素和其他应激诱导化学物质的生存中发挥关键作用。这些结果表明，对抗生素和环境胁迫的抗性增加的选择可能无意中选择了鲍曼不动杆菌的毒力增加。
The increasing emergence of antibiotic-resistant bacterial pathogens represents a serious risk to human health and the entire health care system. Many currently circulating strains of Acinetobacter baumannii exhibit resistance to multiple antibiotics. A key limitation in combating A. baumannii is that our understanding of the molecular mechanisms underlying the pathogenesis of A. baumannii is lacking. To identify potential virulence determinants of a contemporary multidrug-resistant isolate of A. baumannii, we used transposon insertion sequencing (TnSeq) of strain AB5075. A collection of 250,000 A. baumannii transposon mutants was analyzed for growth within Galleria mellonella larvae, an insect-based infection model. The screen identified 300 genes that were specifically required for survival and/or growth of A. baumannii inside G. mellonella larvae. These genes encompass both known, established virulence factors and several novel genes. Among these were more than 30 transcription factors required for growth in G. mellonella. A subset of the transcription factors was also found to be required for resistance to antibiotics and environmental stress. This work thus establishes a novel connection between virulence and resistance to both antibiotics and environmental stress in A. baumannii. Acinetobacter baumannii is rapidly emerging as a significant human pathogen, largely because of disinfectant and antibiotic resistance, causing lethal infection in fragile hosts. Despite the increasing prevalence of infections with multidrug-resistant A. baumannii strains, little is known regarding not only the molecular mechanisms that allow A. baumannii to resist environmental stresses (i.e., antibiotics and disinfectants) but also how these pathogens survive within an infected host to cause disease. We employed a large-scale genetic screen to identify genes required for A. baumannii to survive and grow in an insect disease model. While we identified many known virulence factors harbored by A. baumannii, we also discovered many novel genes that likely play key roles in A. baumannii survival of exposure to antibiotics and other stress-inducing chemicals. These results suggest that selection for increased resistance to antibiotics and environmental stress may inadvertently select for increased virulence in A. baumannii.