Toolbox for hybrid variable-bandwidth bacterio-mimetic antimicrobials

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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.