Manipulating a Virulence Switch to Combat Acinetobacter baumannii Infections

操纵毒力开关来对抗鲍曼不动杆菌感染

• 批准号: 10620146
• 负责人: Philip N. Rather
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620146
• 关键词: Acinetobacter; Acinetobacter baumannii; Animal Model; Antibiotic Resistance; Antibiotics; Attenuated; Attenuated Vaccines; Automobile Driving; Back; Cells; Complex; Development; Disease; Exhibits; Family; Frequencies; Funding; Gene Expression; Genes; Hospitals; Human; Individual; Infection; Intervention; Lighting; Lung; Lung infections; Microbial Biofilms; Military Hospitals; Military Personnel; Modeling; Multi-Drug Resistance; Mus; Pathway interactions; Phenotype; Prevention; Regulation; Regulatory Pathway; Regulon; Resistance; Role; Signal Transduction; Testing; Vaccines; Variant; Virulence; Virulent; Work; World Health Organization; attenuation; capsule; cell motility; cell type; combat; comparative; emerging pathogen; experimental study; high throughput screening; immunogenic; in vivo; inhibitor; military injury; mutant; novel; novel therapeutics; overexpression; pathogen; pathogenic bacteria; quorum sensing; resistant strain; small molecule; transcriptome; virulence gene

Acinetobacter baumannii is a nosocomial pathogen responsible for an increasing number of infections in VA, civilian and military hospitals. This proposal will extend novel findings in our lab, where work has identified that A. baumannii cells can exist in two subpopulations, one virulent and one avirulent. These subpopulations can rapidly interconvert and we have identified a central regulator of this switch. This TetR-type regulator is encoded by the ABUW_1645 gene and overexpression of this regulator drives cells from the virulent state to the avirulent state where they are now locked. Previous work identified a complex regulatory network where a LysR-type regulator (ABUW_1132) activates ABUW_1645 expression and two additional TetR regulators, encoded by ABUW_1959 and ABUW_2818, which drives cells into the avirulent state. Individual overexpression of either ABUW_1959 or ABUW_2818 also drives virulent cells into an avirulent state, where they are now locked. The identification of this switch controlling virulence and our understanding of its regulation now paves the way for translational interventions to exploit this switch and render cells avirulent. First, we will identify genes controlled by all three regulators that contribute to the loss of virulence. The role of these genes will be tested by constructing the appropriate mutants and testing in animal models. Next, we will take advantage of the locked avirulent state to develop a live attenuated A. baumannii vaccine strain. Lastly, small molecules that drive cells from the virulent to the avirulent state will be identified by high-throughput screening. Ultimately, these inhibitors may result in the development of novel therapies to disable virulence in this increasingly important bacterial pathogen.

鲍曼不动杆菌是一种医院内病原体，导致鲍曼不动杆菌不断增加 退伍军人管理局、民用和军队医院的感染人数。该提案将 扩展了我们实验室的新发现，我们的工作已确定鲍曼不动杆菌细胞 可以存在两种亚群，一种是有毒力的，一种是无毒力的。这些 亚群可以快速相互转化，我们已经确定了一个中央调节器 这个开关。该 TetR 型调节因子由 ABUW_1645 基因编码， 该调节因子的过度表达会驱动细胞从有毒状态转变为无毒状态 说明它们现在被锁定的位置。之前的工作确定了复杂的监管 LysR 型调节器 (ABUW_1132) 激活 ABUW_1645 的网络 表达式和两个额外的 TetR 调节因子，由 ABUW_1959 和 ABUW_2818，驱动细胞进入无毒状态。个人 ABUW_1959 或 ABUW_2818 的过度表达也会驱动有毒细胞 进入无毒状态，现在它们被锁定。本次鉴定 控制毒力的开关以及我们对其调节的理解现在为我们铺平了道路 翻译干预的一种方式是利用这种开关并使细胞无毒。 首先，我们将确定由所有三个调节因子控制的基因，这些调节因子有助于 失去毒力。这些基因的作用将通过构建 适当的突变体并在动物模型中进行测试。接下来我们将利用 锁定无毒状态以开发鲍曼不动杆菌减毒活疫苗 拉紧。最后，驱动细胞从毒力转变为无毒力的小分子 状态将通过高通量筛选来鉴定。最终，这些抑制剂 可能会导致开发出新的疗法来消除这种病毒的毒力 日益重要的细菌病原体。

项目成果

Regulation of the swarming inhibitor disA in Proteus mirabilis.

奇异变形杆菌中群聚抑制剂 disA 的调节。

• DOI: 10.1128/jb.00039-13
• 发表时间: 2013
• 期刊: Journal of bacteriology
• 影响因子: 3.2
• 作者: Szostek,BreeA;Rather,PhilipN
• 通讯作者: Rather,PhilipN

Expression of the DisA amino acid decarboxylase from Proteus mirabilis inhibits motility and class 2 flagellar gene expression in Escherichia coli.

来自奇异变形杆菌的 DisA 氨基酸脱羧酶的表达抑制大肠杆菌中的运动和 2 类鞭毛基因表达。

• DOI: 10.1016/j.resmic.2012.09.002
• 发表时间: 2013
• 期刊: Research in microbiology
• 影响因子: 2.6
• 作者: Stevenson,LindsayG;Szostek,BreeA;Clemmer,KatyM;Rather,PhilipN
• 通讯作者: Rather,PhilipN

Stochastic activation of a family of TetR type transcriptional regulators controls phenotypic heterogeneity in Acinetobacter baumannii.

• DOI: 10.1093/pnasnexus/pgac231
• 发表时间: 2022-11
• 期刊: PNAS NEXUS
• 作者: Perez-Varela, Maria;Tierney, Aimee R. P.;Dawson, Emma;Hutcheson, Anna R.;Tipton, Kyle A.;Anderson, Sarah E.;Haldopoulos, Marina E.;Song, Shaina;Tomlinson, Brooke R.;Shaw, Lindsey N.;Weiss, David S.;Kim, Minsu;Rather, Philip N.
• 通讯作者: Rather, Philip N.