CAREER: Designing Quorum Sensing Modulators for Lactobacillus plantarum to Probe Interspecies and Host-Microbe Interactions

在化学系生命过程化学项目的支持下，摩拉维亚学院的Michael A. Bertucci博士正在研究人体内细菌中介导细胞间通讯的化学信号。这些共生细菌不会引起感染。然而，这些细菌的存在或类型的不平衡与胃肠道疾病、妇科疾病和对感染性细菌的更大易感性有关。贝尔图奇博士的研究重点是这些共生微生物中的一个子集，即乳酸菌，它通过作为细菌密度信号的小肽来调节整个菌落的交流。本研究的预期结果包括合成这些肽的新方法，能够增强或沉默乳酸菌细胞间通信的肽探针文库的开发，以及对这些通信途径如何影响这些细菌引起的积极健康效应的更深入了解。作为这个跨学科研究项目的一部分，计划中的教育活动包括一个新的基于课程的研究经验和摩拉维亚学院的第一年研究指导项目，摩拉维亚学院是一个主要的本科机构，为大量的第一代和符合佩尔资格的学生提供服务。其他教育目标包括利用社交媒体提高科学参与度和素养，并为在以教学为重点的机构寻求职业的研究生和博士后建立科学教育培训计划。本项目的目的是合成和评估基于肽的调节剂，用于普遍存在的密度依赖的化学通信过程，即细菌群体感应（QS）。本研究的模型系统是植物乳杆菌（L. plantarum），这是一种具有益生菌特性和由环肽（LamD）控制的QS途径的物种。首先研究影响肽环化的因素，以开发一种合成肽硫内酯的新方法。然后，将合成天然硫内酯LamD衍生物，对无法产生LamD的工程植物l.s plantarum突变体进行一系列系统的结构-活性扫描。通过利用这些数据，将开发出有效的QS激动剂和拮抗剂，并在共培养实验中用于调节QS，以表征QS对种间、属间和宿主-微生物相互作用的影响。完成所描述的研究目标有可能促进对共生细菌细胞间信号传导的化学基础的理解，包括这种信号传导如何决定混合微生物种群的生态变化。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

With the support of the Chemistry of Life Processes Program in the Division of Chemistry, Dr. Michael A. Bertucci of Moravian College is studying chemical signals that mediate cell-cell communication in bacteria present within the human body. These commensal bacteria do not cause infection. However, an imbalance in the presence or types of these bacteria has been linked to gastrointestinal disorders, gynecological disorders, and a greater susceptibility to infectious bacteria. Dr. Bertucci’s work focuses on a subset of these commensal microbes, known as lactic-acid bacteria, that regulate colony-wide communication through small peptides that serve as signals of bacterial density. The anticipated outcomes of this investigation include a novel method for synthesizing these peptides, the development of a library of peptide probes capable of enhancing or silencing lactic-acid bacteria cell-cell communication, and a greater understanding of how these communication pathways influence the positive health effects elicited by these bacteria. As a part of this interdisciplinary research program, planned education activities include a new course-based research experience and first-year research mentorship program at Moravian College, a primarily undergraduate institution that serves a significant population of first-generation and Pell-eligible students. Additional educational goals include leveraging social media to increase scientific engagement and literacy and establishing a science education training program for graduate and post-doctoral students seeking careers at teaching-focused institutions. The objective of this project is to synthesize and evaluate peptide-based modulators for the ubiquitous density-dependent chemical communication process known as bacterial quorum sensing (QS). The model system for this investigation is Lactobacillus plantarum (L. plantarum), a species with documented probiotic properties and a QS pathway controlled by a cyclic peptide (LamD). The stated objective will be accomplished by first studying the factors affecting peptide cyclization to develop a novel method for the synthesis of peptide thiolactones. Then, derivatives of native thiolactone LamD will be synthesized to conduct a series of systematic structure-activity scans in engineered L. plantarum mutants incapable of producing LamD. By harnessing this data, potent QS agonists and antagonists will be developed and employed to modulate QS in co-culture experiments to characterize the influence of QS on interspecies, intergenus, and host-microbe interactions. Completion of the described research objectives has the potential to advance understanding of the chemical basis for intercellular signaling in commensal bacteria, including how this signaling dictates ecological changes in mixed microbial populations.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.