Structure-function-guided design of synthetic peptides with anti-infective activity derived from wasp venom

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dc.authoridOztekin, Sebahat/0000-0003-0859-1776
dc.authoridAgeitos, Lucia/0000-0002-2422-3773
dc.authoridTorres, Marcelo/0000-0002-6165-9138
dc.contributor.authorBoaro, Andreia
dc.contributor.authorAgeitos, Lucia
dc.contributor.authorTorres, Marcelo Der Torossian
dc.contributor.authorBlasco, Esther Broset
dc.contributor.authorOztekin, Sebahat
dc.contributor.authorde la Fuente-Nunez, Cesar
dc.date.accessioned2024-10-04T18:53:48Z
dc.date.available2024-10-04T18:53:48Z
dc.date.issued2023
dc.departmentBayburt Üniversitesien_US
dc.description.abstractAntimicrobial 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.en_US
dc.description.sponsorshipProcter Gamble Company; BBRF Young Investigator Grant; Nemirovsky Prize; Perelman School of Medicine at the University of Pennsylvania; Langer Prize (AIChE Foundation); National Institute of General Medical Sciences of the National Institutes of Health [R35GM138201]; Defense Threat Reduction Agency (DTRA) [HDTRA11 810041, HDTRA1-21-1-0014, HDTRA1-23-1-0001]; Xunta de Galicia; social European funding (FSE) of the European Union [P30-AR069589]; United Therapeutics; Turkish Council of Higher Education (CoHE) Research Scholarship for Doctoral Studies Abroad [2016/10585-4]; Fundacao de Amparo aPesquisa do Estado de Sao Paulo (FAPESP); Penn Skin Biology and Diseases Resource-based Center - NIH/NIAMS [2019/15871-3]; University of Pennsylvania Perelman School of Medicine; [ED481A-2019/081]; [YOK-YUDAB/2019]en_US
dc.description.sponsorshipC.d.l.F.-N. holds a Presidential Professorship at the University of Pennsylvania and acknowledges funding from the Procter & Gamble Company, United Therapeutics, a BBRF Young Investigator Grant, the Nemirovsky Prize, the Penn Health-Tech Accelerator Award, and the Dean's Innovation Fund from the Perelman School of Medicine at the University of Pennsylvania. Research reported in this publication was supported by the Langer Prize (AIChE Foundation) , the National Institute of General Medical Sciences of the National Institutes of Health under award number R35GM138201, and the Defense Threat Reduction Agency (DTRA; HDTRA11 810041, HDTRA1-21-1-0014, and HDTRA1-23-1-0001) . We thank Dr. Karen Pepper for editing the manuscript and de la Fuente Lab members for insightful discussions. We thank the Fundacao de Amparo aPesquisa do Estado de Sao Paulo (FAPESP) for the provided grants (A.B. 2016/10585-4 and 2019/15871-3) , Xunta de Galicia for a pre-doctoral fellowship 2019 co-funded with the social European funding (FSE) of the European Union (ED481A-2019/081) , and Turkish Council of Higher Education (CoHE) Research Scholarship for Doctoral Studies Abroad (YOK-YUDAB/2019) . We thank Dr. Mark Goulian for kindly donating E. coli JW2703 (hypermutant strain) DmutSkan. (from the Keio collection) . Keratinocytes were purchased from the Penn Skin Biology and Diseases Resource-based Center (SBDRC) and, as a result, support for this work was also provided by the Penn Skin Biology and Diseases Resource-based Center, funded by NIH/NIAMS grant P30-AR069589 and the University of Pennsylvania Perelman School of Medicine. All figures were prepared in BioRender.com .en_US
dc.identifier.doi10.1016/j.xcrp.2023.101459
dc.identifier.issn2666-3864
dc.identifier.issue7en_US
dc.identifier.pmid38239869en_US
dc.identifier.urihttps://doi.org/10.1016/j.xcrp.2023.101459
dc.identifier.urihttp://hdl.handle.net/20.500.12403/3708
dc.identifier.volume4en_US
dc.identifier.wosWOS:001047018200001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofCell Reports Physical Scienceen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectCationic Antimicrobial Peptidesen_US
dc.subjectPseudomonas-Aeruginosaen_US
dc.subjectPolycationic Peptidesen_US
dc.subjectResistanceen_US
dc.subjectBacterialen_US
dc.subjectMembraneen_US
dc.subjectAntibioticsen_US
dc.subjectMechanismen_US
dc.subjectSynergyen_US
dc.subjectAnalogsen_US
dc.titleStructure-function-guided design of synthetic peptides with anti-infective activity derived from wasp venomen_US
dc.typeArticleen_US

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