Toolbox for hybrid variable-bandwidth bacterio-mimetic antimicrobials

非技术：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，旨在开发一种工具箱，用于制造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，从而控制有毒菌株而不伤害共生菌株。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，但针对所有感兴趣的物种制造个体化靶向抗生素是不现实的。在自然界中，细菌制造多功能抗生素来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“窗口”的分子中，在特定的环境条件下针对多种物种。来自宿主相关微生物群落的抗菌剂通过抑制致病菌而不损害宿主细胞或有益的共生菌对人类健康产生有益影响。这些方法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“共栖”种群。提出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。建议的研究课题将被纳入PI的高级本科/研究生课程。此外，将利用几种机制，包括一种新型的“反向外展”，向PI就读的一所经济条件较差的高中提供教育模块。该共同负责人是该校的一名驻校教师，将利用这一角色来扩大更多不同学生群体对STEM主题的参与。技术方面：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，通过控制有毒菌株而不伤害共生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。有了这份合同，研究人员将开发：a)使用ph可切换电荷具有“阈值”活动剖面的基线可调amp；b)具有低-高-低“窗口”活性谱的抗菌肽，使用ph可切换的疏水性和电荷；c)同时攻击协同细菌目标以增强活性的多功能抗菌剂。为了实现这些目标，氨基酸残基将被改变，从而影响amp的疏水和/或阳离子活性，从而使这些特性受到环境条件的减弱。研究计划是通过在amp中特定位置的精氨酸、组氨酸和/或赖氨酸残基上加入掩膜基团，制造出在特定和可调的pH值下开启和关闭的螺旋amp。这种掩蔽基团将直接控制酸解离常数（pKa），使残基带正电并激活AMP。本研究还将针对在特定pH范围内生长的菌落内的细菌物种，使用设计的仅在有限pH范围内开启的AMP，在AMP的战略位置使用可切割的酪氨酸和/或色氨酸残基掩蔽基团。最后，在不同生态位环境的电荷/疏水性设计规则的指导下，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。这将允许靶向不摄取抗生素的厌氧细菌，绕过诸如外排泵的耐药机制，并将抗生素转运到居住在人类宿主细胞内的细菌中。就更广泛的影响而言，该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就业机会，并有助于培养学术和工业生涯。此外，研究结果将被纳入PI的高级本科/研究生课程。通过一种新型的“反向推广”项目，为PI家乡一所经济条件较差的高中提供丰富的教育模块。共同负责人是该校的一名驻校教师，她计划扩大不同学生群体在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.