Toolbox for hybrid variable-bandwidth bacterio-mimetic antimicrobials

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授予，旨在开发一种工具箱，用于创造具有高度特异性的新型抗菌剂，以控制微生物群落中的物种分布，从而控制有毒菌株，而不伤害细菌菌株。目前的方法使用有效的广谱抗生素和/或药物，抑制或杀死有益的和致病的物种。尽管物种特异性抗生素原则上是可能的，但使抗生素针对所有感兴趣的物种进行个体化靶向是不实际的。在自然界中，细菌制造多功能抗生素，以抑制竞争相同环境资源的密切相关菌株。拟议的研究是模仿这种方法，并构建具有可调抗菌特性的分子，并将它们整合到具有可调抗菌活性的分子中，以对抗特定环境条件下的多个物种。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的肠道细菌而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“繁殖”种群。建议的多学科研究课题有利于培养学生从事不同的学术和工业职业。拟议的研究课题将纳入PI的高级本科生/研究生课程。此外，还将利用多种机制，包括一种新型的“反向推广”，向PI就读的一所经济条件较差的高中提供教育模块。co-PI是校园内的住校教师，并将利用这一角色扩大更多不同学生群体参与STEM主题技术：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，通过控制毒力菌株而不伤害微生物菌株来控制微生物群落中的物种分布。这项研究计划利用了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。有了这个奖项，研究人员将开发：a）基线可调AMP，具有使用pH可切换电荷的“阈值”活性特征; B）具有使用pH可切换疏水性和电荷的lo-hi-lo“窗口”活性特征的抗菌肽;以及c）同时击中协同细菌靶标以放大活性的多功能抗菌剂。为了实现这些目标，将改变有助于AMP的疏水和/或阳离子活性的氨基酸残基，使得这些性质被环境条件减弱。 该研究计划是通过在AMP的特定位置的精氨酸、组氨酸和/或赖氨酸残基上引入掩蔽基团，使螺旋AMP在特定和可调的pH值下打开和关闭。 这种掩蔽基团将直接控制残基带正电荷并激活AMP的酸解离常数（pKa）。这项研究还将针对在特定pH范围内生长的菌落内的细菌物种，使用仅在有限pH范围内打开的设计AMP，在AMP的战略位置使用酪氨酸和/或色氨酸残基的可裂解掩蔽基团。最后，将分子伴侣传统抗生素进入细胞的细胞穿透肽转运蛋白序列的设计将由不同生态位环境的电荷/疏水性设计规则指导。这将允许靶向不摄取抗生素的厌氧菌，以规避耐药机制，如外排泵，并将抗生素转运到驻留在人类宿主细胞内的细菌中。在更广泛的影响方面，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，由此产生的结果将被纳入PI的高级本科/研究生课程。将通过一种新型的“反向推广”方案，向PI家乡的一所经济困难的高中提供充实教育模块。co-PI是校园内的一个住校教师，计划扩大多元化学生群体在STEM领域的参与。

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.