@article{fbf33441c56443afac1d088501b29def,
title = "Two distinct amphipathic peptide antibiotics with systemic efficacy",
abstract = "Antimicrobial peptides are important candidates for developing new classes of antibiotics because of their potency against antibiotic-resistant pathogens. Current research focuses on topical applications and it is unclear how to design peptides with systemic efficacy. To address this problem, we designed two potent peptides by combining database-guided discovery with structure-based design. When bound to membranes, these two short peptides with an identical amino acid composition can adopt two distinct amphipathic structures: A classic horizontal helix (horine) and a novel vertical spiral structure (verine). Their horizontal and vertical orientations on membranes were determined by solid-state 15N NMR data. While horine was potent primarily against gram-positive pathogens, verine showed broad-spectrum antimicrobial activity. Both peptides protected greater than 80% mice from infection-caused deaths. Moreover, horine and verine also displayed significant systemic efficacy in different murine models comparable to conventional antibiotics. In addition, they could eliminate resistant pathogens and preformed biofilms. Significantly, the peptides showed no nephrotoxicity to mice after intraperitoneal or intravenous administration for 1 wk. Our study underscores the significance of horine and verine in fighting drug-resistant pathogens.",
keywords = "Antibiotic resistance, NMR, Nephrotoxicity, Peptide antibiotics, Systemic efficacy",
author = "Narayana, {Jayaram Lakshmaiah} and Biswajit Mishra and Tamara Lushnikova and Qianhui Wu and Chhonker, {Yashpal S.} and Yingxia Zhang and D. Zarena and Salnikov, {Evgeniy S.} and Xiangli Dang and Fangyu Wang and Caitlin Murphy and Foster, {Kirk W.} and Santhi Gorantla and Burkhard Bechinger and Murry, {Daryl J.} and Guangshun Wang",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Dr. Paul D. Fey for bacterial strains, helpful suggestions, and manuscript editing; Drs. Manju George and David Oupicky for help with our proposed rat study protocol; the University of Nebraska Medical Center Core Facilities (nanomaterial characterization, tissue, confocal microscopy, NMR, and electron microscopy) for excellent service; and Ms. Yan Cheng and Dr. Lili Guo for humanized mouse generation. This work was supported by Grants AI128230 and AI105147 from the National Institutes of Health and, in part, by a Nebraska Research Initiative Proof of Concept (to G.W.). Humanized mice were supported by R24 OD018546-01 (to S.G.). For the solid-state NMR study, B.B. is gratefully supported by the Agence Nationale de la Recherche (projects Biosupramol 17-CE18-0033-3 and the LabEx Chemistry of Complex Systems 10-LABX-0026_CSC) and the R{\'e}seau Th{\'e}matique de Recherche Avanc{\'e}e International Center of Frontier Research in Chemistry. Visiting scholars were supported by the India Raman Postdoctoral Fellowship (D.Z. from Jawaharlal Nehru Technological University Ananta-pur), Henan Visiting Scholarship (F.W. from Henan Academy of Agricultural Sciences), China Scholarship Council (Y.Z. from Hainan University and X.D. from Anhui Agricultural University), and Yangzhou University Scholarship (Q.W. from Yangzhou University). Funding Information: We thank Dr. Paul D. Fey for bacterial strains, helpful suggestions, and manuscript editing; Drs. Manju George and David Oupicky for help with our proposed rat study protocol; the University of Nebraska Medical Center Core Facilities (nanomaterial characterization, tissue, confocal microscopy, NMR, and electron microscopy) for excellent service; and Ms. Yan Cheng and Dr. Lili Guo for humanized mouse generation. This work was supported by Grants AI128230 and AI105147 from the National Institutes of Health and, in part, by a Nebraska Research Initiative Proof of Concept (to G.W.). Humanized mice were supported by R24 OD018546-01 (to S.G.). For the solid-state NMR study, B.B. is gratefully supported by the Agence Nationale de la Recherche (projects Biosupramol 17-CE18-0033-3 and the LabEx Chemistry of Complex Systems 10-LABX-0026_CSC) and the R?seau Th?matique de Recherche Avanc?e International Center of Frontier Research in Chemistry. Visiting scholars were supported by the India Raman Postdoctoral Fellowship (D.Z. from Jawaharlal Nehru Technological University Anantapur), Henan Visiting Scholarship (F.W. from Henan Academy of Agricultural Sciences), China Scholarship Council (Y.Z. from Hainan University and X.D. from Anhui Agricultural University), and Yangzhou University Scholarship (Q.W. from Yangzhou University). Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = aug,
day = "11",
doi = "10.1073/pnas.2005540117",
language = "English (US)",
volume = "117",
pages = "19446--19454",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "32",
}