Synthetic molecular evolution of host cell-compatible, antimicrobial peptides effective against drug-resistant, biofilm-forming bacteria.

Autor:	Starr CG; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112., Ghimire J; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112., Guha S; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112., Hoffmann JP; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112., Wang Y; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112., Sun L; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112., Landreneau BN; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112., Kolansky ZD; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112., Kilanowski-Doroh IM; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112., Sammarco MC; Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112., Morici LA; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA 70112., Wimley WC; Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112; wwimley@tulane.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Apr 14; Vol. 117 (15), pp. 8437-8448. Date of Electronic Publication: 2020 Apr 02.
DOI:	10.1073/pnas.1918427117
Abstrakt:	Novel classes of antibiotics and new strategies to prevent and treat infections are urgently needed because the rapid rise in drug-resistant bacterial infections in recent decades has been accompanied by a parallel decline in development of new antibiotics. Membrane permeabilizing antimicrobial peptides (AMPs) have long been considered a potentially promising, novel class of antibiotic, especially for wound protection and treatment to prevent the development of serious infections. Yet, despite thousands of known examples, AMPs have only infrequently proceeded as far as clinical trials, especially the chemically simple, linear examples. In part, this is due to impediments that often limit their applications in vivo. These can include low solubility, residual toxicity, susceptibility to proteolysis, and loss of activity due to host cell, tissue, and protein binding. Here we show how synthetic molecular evolution can be used to evolve potentially advantageous antimicrobial peptides that lack these impediments from parent peptides that have at least some of them. As an example of how the antibiotic discovery pipeline can be populated with more promising candidates, we evolved and optimized one family of linear AMPs into a new generation with high solubility, low cytotoxicity, potent broad-spectrum sterilizing activity against a panel of gram-positive and gram-negative ESKAPE pathogens, and antibiofilm activity against gram-positive and gram-negative biofilms. The evolved peptides have these activities in vitro even in the presence of concentrated host cells and also in vivo in the complex, cell- and protein-rich environment of a purulent animal wound model infected with drug-resistant bacteria. Competing Interests: Competing interest statement: Authors C.G.S., J.G., S.G., and W.C.W. are inventors on a US Patent application filed by Tulane University.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu