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.

由鲍曼不动杆菌等革兰氏阴性病原体引起的医院感染已成为 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不愈合感染 伤口感染最终可能导致败血症。值得关注的是生活频率的增加—— 耐药鲍曼不动杆菌引起的威胁性感染，加强了对新疗法的需求 接近。最近的研究表明，鲍曼不动杆菌类群在临床环境中丰富，并且 微生物多样性的减少导致抗菌素耐药性增加。然而，人们对此知之甚少 从这些环境中分离出来的不动杆菌之间的生物和物理相互作用。 直接从大学患者获得的越来越多的不动杆菌分离株的特征 密歇根医院系统在 5 年的时间里已经鉴定出鲍曼不动杆菌的“捕食者”菌株 抑制敏感（“猎物”）不动杆菌菌株的生长。该表型表现为一个区域 清除来自集中接种的捕食者的敏感细菌（嵌入软琼脂中） 菌株。含有属于核糖体合成家族的新型肽毒素的粗提物 翻译后修饰肽 (RiPP) 可以从捕食者中分离出来，然后添加到猎物中 菌株导致细胞接触无关的生长抑制。我们的初步数据表明 预测该 RiPP 的合成、修饰和分泌所需的基因的存在， 新型肽毒素，比较少见。对我们收集的菌株的筛选表明，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。相比之下，包括多药在内的几种鲍曼不动杆菌菌株 耐药鲍曼不动杆菌分离株以及皮蒂不动杆菌菌株对杀灭敏感。这 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 确定肽毒素的性质及其分泌机制。此外，实验还有 旨在揭示毒素如何进入敏感菌株以及通过什么机制抑制其生长。这些 研究将增进我们对毒素作用的理解，并对以下方面具有重大的转化意义： 精准药物治疗的潜力，因为使用毒素或其变体可能是一种有前途的手段 对抗多重耐药鲍曼不动杆菌引起的感染。