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，Michael A.摩拉维亚学院的Bertucci正在研究介导人体内细菌细胞间通讯的化学信号。 这些肠道细菌不会引起感染。 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。 Bertucci博士的工作重点是这些肠道微生物的一个子集，即乳酸菌，它们通过作为细菌密度信号的小肽来调节整个菌落的通讯。 这项研究的预期成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讯的肽探针库的开发，以及对这些通讯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计划的一部分，计划的教育活动包括一个新的课程为基础的研究经验和第一年的研究导师计划在摩拉维亚学院，主要是本科院校，服务于第一代和佩尔合格的学生的显着人口。 其他教育目标包括利用社交媒体来提高科学参与和素养，并为在以教学为重点的机构寻求职业的研究生和博士后学生建立科学教育培训计划。 本项目的目的是合成和评估肽基调节剂的普遍存在的密度依赖性化学通讯过程称为细菌群体感应（QS）。 本研究的模式系统是植物乳杆菌（Lactobacillus plantarum）。plantarum），一种具有记录的益生菌特性和由环肽（LamD）控制的QS途径的物种。本论文首先研究了影响肽环化反应的因素，开发了一种合成肽硫内酯的新方法。 然后，合成天然硫内酯LamD的衍生物，在工程菌中进行一系列系统的构效扫描。植物突变体不能产生LamD。 通过利用这些数据，将开发有效的QS激动剂和拮抗剂，并用于在共培养实验中调节QS，以表征QS对种间、属间和宿主-微生物相互作用的影响。 上述研究目标的完成有可能促进对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NSF的法定使命，并被认为值得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来支持。

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.