Toolbox for hybrid variable-bandwidth bacterio-mimetic antimicrobials

混合可变带宽仿细菌抗菌剂工具箱

• 批准号: 1411329
• 负责人: Gerard Wong
• 金额: $ 50万
• 依托单位: University of California-Los Angeles
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1411329&HistoricalAwards=false
• 关键词: Toolbox; hybrid; variable; bandwidth; bacterio

Nontechnical: This award by the Biomaterials Program in the Division of Materials Research to University of California Los Angeles is to develop a toolbox for creating new antimicrobials with high specificity to control the distributions of species in microbial communities in controlling virulent strains without harming commensal strains. Current approaches use potent broad-spectrum antibiotics and/or drug, inhibiting or killing beneficial and pathogenic species alike. Although species-specific antibiotics are in principle possible, it is not practical to make antibiotics for individualized targeting for all species of interest. In nature, bacteria make multi-functional antibiotics to inhibit closely related strains competing for the same environmental resources. The proposed research is to mimic this approach, and to build molecules with tunable antimicrobial properties, and integrate them into molecules with adjustable "windows" of antimicrobial activity against multiple species within a specific set of environmental condition. Antimicrobials from host-associated microbial communities would have beneficial impact on human health by inhibiting pathogenic bacteria without harming host cells or beneficial commensal bacteria. These approaches would have the potential to regulate complex microbial colonies, and leverage the natural competition between bacterial species to "commensalize" the population. The proposed multidisciplinary research topic is conducive to training students for different academic and industrial careers. The proposed research topics will be incorporated into the PI's advanced undergraduate/graduate classes. Additionally, educational modules will be provided to an economically disadvantaged high school where the PI attended using several mechanisms, including a new type of "reverse outreach". The co-PI is a faculty-in-residence at the campus, and will leverage this role to broaden the participation of more diverse student populations in STEM topicsTechnical: This research aims to develop a toolbox for creating new antimicrobial peptides with high specificity to control species distributions in microbial communities by controlling virulent strains without harming commensal strains. This research program leverages recently developed sequence design rules for antimicrobial peptides, where charge and hydrophobicity are both necessary conditions for antimicrobial peptide (AMP) activity. With this award, the researchers will develop: a) baseline tunable AMPs with a "threshold" activity profile using pH-switchable charge; b) antimicrobial peptides with lo-hi-lo "window" activity profile using pH-switchable hydrophobicity and charges; and c) multi-functional antimicrobials that simultaneously hit synergistic bacterial targets to amplify activity. To achieve these goals, aminoacid residues will be altered that contribute to the hydrophobic and/or cationic activities of AMPs such that these properties are attenuated by environmental conditions. The research plan is to make helical AMPs that turn on and off at specific and tunable pH values, by incorporating masking groups at arginine, histidine and/or lysine residues at specific locations in AMPs. Such masking groups will directly control the acid dissociation constant (pKa) at which residues become positively charged and activating the AMP. This research will also target bacterial species within a colony that thrive at a specific pH range using designed AMPs that only turn on within a finite pH range, using cleavable masking groups for tyrosine and/or tryptophan residues at strategic locations in AMPs. Finally, the design of cell-penetrating peptide transporter sequences to chaperone traditional antibiotics into cells will be guided by the charge/hydrophobicity design rules for different niche environments. This will allow in targeting anaerobic bacteria that do not uptake antibiotics, to circumvent resistance mechanisms such as efflux pumps, and to transport antibiotics into bacteria that reside within human host cells. With respect to broader impacts, the multi-disciplinary nature of the research will provide students with ample educational and career opportunities in this emerging field, and would be conducive to training for academic and industrial careers. In addition, results from this will be incorporated into the PI's advanced undergraduate/graduate classes. Enrichment educational modules will be provided to an economically disadvantaged high school in the PI's hometown with a new type of "reverse outreach" program. The co-PI, a faculty-in-residence at the campus, plans to broaden the participation of a diverse student population in STEM areas.

非技术性：该奖项由加州大学洛杉矶分校材料研究部生物材料项目颁发，旨在开发一个工具箱，用于创建具有高特异性的新型抗菌剂，以控制微生物群落中物种的分布，从而在不伤害共生菌株的情况下控制剧毒菌株。目前的方法使用强效广谱抗生素和/或药物，抑制或杀死有益和致病物种。虽然物种特异性抗生素原则上是可能的，但制造针对所有感兴趣物种的个体化抗生素是不切实际的。在自然界中，细菌会产生多功能抗生素来抑制密切相关的菌株争夺相同的环境资源。拟议的研究是模仿这种方法，构建具有可调节抗菌特性的分子，并将它们整合到具有可调节抗菌活性“窗口”的分子中，以对抗特定环境条件下的多种物种。来自宿主相关微生物群落的抗菌剂将通过抑制病原菌而不损害宿主细胞或有益共生菌来对人类健康产生有益影响。这些方法将有可能调节复杂的微生物菌落，并利用细菌物种之间的自然竞争来“共生”种群。所提出的多学科研究课题有利于为不同学术和工业职业培养学生。拟议的研究课题将纳入PI的高级本科/研究生课程。此外，还将通过多种机制向 PI 就读的经济贫困高中提供教育模块，其中包括新型“反向推广”。联合首席研究员是校园的驻校教师，将利用这一角色扩大更多不同学生群体对 STEM 主题的参与。技术：本研究旨在开发一个工具箱，用于创建具有高特异性的新型抗菌肽，通过在不损害共生菌株的情况下控制剧毒菌株来控制微生物群落中的物种分布。该研究计划利用最近开发的抗菌肽序列设计规则，其中电荷和疏水性都是抗菌肽（AMP）活性的必要条件。凭借这一奖项，研究人员将开发： a) 使用 pH 可切换电荷具有“阈值”活性特征的基线可调 AMP； b) 使用pH可切换的疏水性和电荷具有lo-hi-lo“窗口”活性特征的抗菌肽； c) 多功能抗菌剂，可同时打击协同细菌靶点以增强活性。为了实现这些目标，将改变有助于 AMP 疏水性和/或阳离子活性的氨基酸残基，从而使这些特性因环境条件而减弱。 该研究计划是通过在 AMP 特定位置的精氨酸、组氨酸和/或赖氨酸残基上掺入掩蔽基团，制造在特定且可调的 pH 值下打开和关闭的螺旋 AMP。 此类掩蔽基团将直接控制酸解离常数 (pKa)，在该常数下残基带正电并激活 AMP。这项研究还将针对菌落内在特定 pH 范围内茁壮成长的细菌物种，使用仅在有限 pH 范围内开启的设计 AMP，在 AMP 的战略位置使用可裂解的酪氨酸和/或色氨酸残基掩蔽基团。最后，将根据不同生态位环境的电荷/疏水性设计规则来设计细胞穿透肽转运蛋白序列，以陪伴传统抗生素进入细胞。这将允许针对不吸收抗生素的厌氧细菌，规避诸如外排泵之类的耐药机制，并将抗生素转运到人类宿主细胞内的细菌中。就更广泛的影响而言，研究的多学科性质将为学生在这一新兴领域提供充足的教育和职业机会，并有利于学术和工业职业的培训。此外，该研究的结果将被纳入 PI 的高级本科生/研究生课程中。通过新型“反向延伸”项目，为PI家乡的一所经济困难高中提供丰富的教育模块。该联合 PI 是校园的常驻教师，计划扩大 STEM 领域多元化学生群体的参与。