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Structure-function-guided design of synthetic peptides with anti-infective activity derived from wasp venomBoaro, AndreiaAgeitos, LuciaTorres, Marcelo Der TorossianBlasco, Esther BrosetOztekin, Sebahatde la Fuente-nunez, CesarAntimicrobial peptides (AMPs) derived from natural toxins and venoms offer a promising alternative source of antibiotics. Here, through structure-function-guided design, we convert two natural AMPs derived from the venom of the solitary eumenine wasp Eu-menes micado into a-helical AMPs with reduced toxicity that kill Gram-negative bacteria in vitro and in a preclinical mouse model. To identify the sequence determinants conferring antimicrobial ac-tivity, an alanine scan screen and strategic single lysine substitutions are made to the amino acid sequence of these natural peptides. These efforts yield a total of 34 synthetic derivatives, including alanine substituted and lysine-substituted sequences with stabilized a-helical structures and increased net positive charge. The resulting lead synthetic peptides kill the Gram-negative pathogens Escheri-chia coli and Pseudomonas aeruginosa (PAO1 and PA14) by rapidly permeabilizing both their outer and cytoplasmic membranes, exhibit anti-infective efficacy in a mouse model by reducing bacte-rial loads by up to three orders of magnitude, and do not readily select for bacterial resistance.CELL PRESS2023-07Articlehttps://rdlopen.rawdatalibrary.net/r/bayburt/14063https://doi.org/10.1016/j.xcrp.2023.101459enCELL REPORTS PHYSICAL SCIENCEinfo:eu-repo/semantics/openAccessinfo:eu-repo/semantics/articlehttps://bayburt-rdlopen.rawdatalibrary.net/tr/items/bayburt/14063