Antagonistic relationships among Acinetobacter isolates

不动杆菌分离株之间的拮抗关系

• 批准号: 10604520
• 负责人: Maria B Sandkvist
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-04 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604520
• 关键词: Acinetobacter; Acinetobacter baumannii; Address; Affect; Agar; Amino Acid Permease; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antimicrobial Resistance; Bacteria; Bacterial Toxins; Behavior; Binding Sites; Biochemical; Bioinformatics; Biological; Biological Assay; Blood; Candidate Disease Gene; Catheters; Cells; Cessation of life; Chemicals; Clinical; Code; Collection; Communicable Diseases; Crude Extracts; DNA; Data; Databases; Dedications; Development; Drug resistance; Environment; Escherichia coli; Experimental Designs; Family; Fluorescence Microscopy; Frequencies; Gene Deletion; Genes; Gram-Negative Bacteria; Growth; Healthcare; Hospitals; Immunocompromised Host; Individual; Infection; Knowledge; Libraries; Life; Mediating; Michigan; Microbial Biofilms; Modification; Molecular; Multi-Drug Resistance; Multidrug-resistant Acinetobacter; Mutagenesis; Mutation; Nature; Nosocomial Infections; Outcome; Pathogenesis; Pathway interactions; Patient Isolation; Patients; Peptides; Pharmacotherapy; Phenotype; Positioning Attribute; Post-Translational Protein Processing; Predisposition; Proteins; Public Health; Publishing; Ribosomes; Role; Sepsis; Siderophores; Single Nucleotide Polymorphism; Site; Stream; System; Testing; Toxin; Traumatic injury; Universities; Urinary tract infection; Variant; Virulence Factors; Wound Infection; bactericide; bacteriocin; combat; gene complementation; genome sequencing; innovation; microbial; microcin; mutant; new therapeutic target; non-healing wounds; novel; novel strategies; novel therapeutic intervention; pathogen; precision drugs; receptor; resistance gene; resistance mechanism; screening; siderophore receptors; three dimensional structure; uptake; ventilator-associated pneumonia

Nosocomial infections caused by gram-negative pathogens such as Acinetobacter baumannii have become a major challenge in the treatment of immunocompromised individuals and patients with traumatic injuries. These infections include ventilator-associated pneumonia, catheter-related urinary tract infections and non-healing wound infections that can ultimately lead to sepsis. Of significant concern is the increasing frequency of life- threatening infections caused by drug resistant A baumannii, reinforcing the need for new therapeutic approaches. Recent studies have shown that A. baumannii taxa are abundant in clinical environments and that decreases in microbial diversity contribute to increased antimicrobial resistance. However, little is known about the biological and physical interactions between Acinetobacter sp isolated from these environments. Characterization of a growing collection of Acinetobacter isolates obtained directly from patients at the University of Michigan Hospital System over a period of 5 years has identified “predator” strains of A. baumannii capable of inhibiting the growth of susceptible (“prey”) Acinetobacter strains. This phenotype is manifested as a zone of clearing of susceptible bacteria – embedded in soft agar - that emanates from centrally inoculated predator strains. Crude extracts containing a novel peptide toxin belonging to the family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) can be isolated from the predator and subsequently added to prey strains resulting in cell contact-independent growth inhibition. Our preliminary data demonstrate that the presence of the genes predicted to be required for the synthesis, modification, and secretion of this RiPP, a novel peptide toxin, is relatively rare. Screening of our strain collection indicate that approximately 3 % carry the genes and display the growth inhibition phenotype. Analysis of available sequences in the NCBI database confirms the relatively scarceness of these genes. In contrast, several A. baumannii strains including multidrug resistant A. baumannii isolates as well as strains of the species Acinetobacter pittii are sensitive to killing. The primary objective of this study is to dissect these antagonistic interactions among Acinetobacter isolates. We aim to determine the nature of the peptide toxin and its mechanism of secretion. In addition, experiments are designed to reveal how the toxin enters susceptible strains and by what mechanism it inhibits their growth. These studies will advance our understanding of the role of the toxin and have significant translational implications with potential for precision drug therapy as the use of the toxin or variants thereof may represent a promising means of combating infections caused by multi-drug resistant A. baumannii.

由革兰氏阴性病原体如鲍曼不动杆菌引起的医院感染已成为一种常见的病原体。 这是治疗免疫功能低下个体和创伤性损伤患者的主要挑战。这些 感染包括呼吸机相关性肺炎、导管相关性尿路感染和 最终导致败血症的伤口感染最令人担忧的是生命的频率越来越高- 耐药鲍曼不动杆菌引起的威胁性感染，加强了对新治疗药物的需求， 接近。最近的研究表明，A.鲍曼不动杆菌分类群在临床环境中是丰富的， 微生物多样性的减少导致抗微生物剂耐药性的增加。然而，人们对 从这些环境中分离的不动杆菌之间的生物和物理相互作用。 直接从大学患者中获得的不动杆菌分离株的特征 密歇根州医院系统的一个研究小组在5年的时间里鉴定出了A.鲍曼不动杆菌 抑制敏感（“猎物”）不动杆菌菌株的生长。这种表型表现为一个区域， 清除敏感细菌-包埋在软琼脂中-来自集中接种的捕食者 菌株含有属于核糖体合成的新肽毒素家族的粗提物， 可以从捕食者中分离出后修饰肽（RIPPs），然后将其添加到猎物中 导致细胞接触非依赖性生长抑制的菌株。我们的初步数据表明， 预测为合成、修饰和分泌该RiPP所需的基因的存在， 新的肽毒素，相对罕见。我们的菌株收集的筛选表明，大约3%携带 基因并显示生长抑制表型。NCBI数据库中可用序列的分析 证实了这些基因的相对稀缺性。与此相反，几个A.鲍曼不动杆菌菌株，包括多药 抗性A.鲍曼不动杆菌分离株以及皮特不动杆菌物种的菌株对杀灭敏感。的 本研究的主要目的是剖析不动杆菌分离株之间的这些拮抗相互作用。我们的目标 以确定肽毒素的性质及其分泌机制。此外，实验 旨在揭示毒素如何进入敏感菌株，以及通过何种机制抑制它们的生长。这些 这些研究将促进我们对毒素作用的理解，并具有重要的翻译意义， 由于毒素或其变体的使用可能代表了一种有希望的手段， 抗多药耐药A.鲍曼不动杆菌。