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的生物材料计划授予，旨在开发一种工具箱，用于创造具有高度特异性的新抗菌剂，以控制微生物群落中的物种分布，从而在不损害共生菌株的情况下控制毒力菌株。目前的方法使用有效的广谱抗生素和/或药物，抑制或杀死有益和致病物种。尽管原则上针对特定物种的抗生素是可能的，但针对所有感兴趣的物种制造针对个性化目标的抗生素是不切实际的。在自然界中，细菌制造多功能抗生素来抑制密切相关的菌株竞争相同的环境资源。建议的研究是模仿这种方法，构建具有可调抗菌特性的分子，并将它们集成到具有可调节的抗微生物活性的分子中，在特定的环境条件下对多种物种具有可调的抗菌活性。来自宿主相关微生物群落的抗菌剂可以在不损害宿主细胞或有益共生菌的情况下抑制病原菌，从而对人类健康产生有益的影响。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。建议的多学科研究课题有利于为不同的学术和行业职业培养学生。建议的研究课题将纳入国际私教的本科生/研究生高级班。此外，还将利用几种机制，包括一种新型的“反向外展”，向一所经济困难的高中提供教育模块。联合PI是校园的常驻教员，并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，用于创造具有高度特异性的新抗菌肽，通过控制毒力菌株而不损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的序列设计规则，其中电荷和疏水性都是抗菌肽(AMP)活性的必要条件。有了这一奖项，研究人员将开发：a)基线可调AMP，使用pH可调电荷的“阈值”活性曲线；b)具有低-嗨-低“窗”活性曲线的抗菌肽，使用pH可调疏水性和电荷；以及c)多功能抗菌剂，可同时击中协同细菌目标以放大活性。为了实现这些目标，氨基酸残基将被改变，从而导致AMP的疏水和/或阳离子活性，从而使这些特性因环境条件而减弱。研究计划是通过在AMP的特定位置加入精氨酸、组氨酸和/或赖氨酸残基的掩蔽基，制造在特定和可调节的pH值下开启和关闭的螺旋AMP。这种掩蔽基团将直接控制残基带正电荷并激活AMP的酸离解常数(PKA)。这项研究还将针对菌落中在特定pH范围内茁壮成长的细菌物种，使用设计的只能在有限的pH范围内打开的AMP，使用AMP中关键位置的酪氨酸和/或色氨酸残基的可切割掩蔽基。最后，传统抗生素进入细胞的穿透性多肽转运体序列的设计将遵循针对不同利基环境的电荷/疏水性设计规则。这将允许针对不吸收抗生素的厌氧细菌，绕过外排泵等耐药机制，并将抗生素输送到驻留在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，并将有助于为学术和工业职业生涯提供培训。此外，这项研究的结果将被纳入PI的高级本科生/研究生课程。通过一项新型的“反向外展”计划，将为PI家乡的一所经济困难的高中提供丰富的教育模块。联合派是该校的常驻教职员工，计划扩大STEM地区不同学生群体的参与。

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.