title: Structure-based redesign of lysostaphin yields potent antistaphylococcal enzymes that evade immune cell surveillance.
abstract: Staphylococcus aureus infections exert a tremendous burden on the health-care system, and the threat of drug-resistant strains continues to grow. The bacteriolytic enzyme lysostaphin is a potent antistaphylococcal agent with proven efficacy against both drug-sensitive and drug-resistant strains; however, the enzyme's own bacterial origins cause undesirable immunogenicity and pose a barrier to clinical translation. Here, we deimmunized lysostaphin using a computationally guided process that optimizes sets of mutations to delete immunogenic T cell epitopes without disrupting protein function. In vitro analyses showed the methods to be both efficient and effective, producing seven different deimmunized designs exhibiting high function and reduced immunogenic potential. Two deimmunized candidates elicited greatly suppressed proliferative responses in splenocytes from humanized mice, while at the same time the variants maintained wild-type efficacy in a staphylococcal pneumonia model. Overall, the deimmunized enzymes represent promising leads in the battle against S. aureus.
authors.affiliation: Thayer School of Engineering, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Blazanovic
authors.affiliation: Thayer School of Engineering, Dartmouth , Hanover, New Hampshire, USA ; Laboratory of Microorganism Engineering, Beijing Institute of Biotechnology , Beijing, People's Republic of China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Computer Science, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Yoonjoo
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Thayer School of Engineering, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: Thayer School of Engineering, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Regina S
authors.initials: RS
authors.lastname: Salvat
authors.affiliation: Program in Experimental and Molecular Medicine, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Osipovitch
authors.affiliation: Department of Microbiology and Immunology, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fields
authors.affiliation: Institute for Immunology and Informatics, University of Rhode Island , Providence, Rhode Island, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Moise
authors.affiliation: Department of Microbiology and Immunology, Dartmouth , Hanover, New Hampshire, USA ; Norris Cotton Cancer Center, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Berwin
authors.affiliation: Department of Microbiology and Immunology, Dartmouth , Hanover, New Hampshire, USA ; Norris Cotton Cancer Center, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Fiering
authors.affiliation: Department of Computer Science, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Bailey-Kellogg
authors.affiliation: Thayer School of Engineering, Dartmouth , Hanover, New Hampshire, USA ; Norris Cotton Cancer Center, Dartmouth , Hanover, New Hampshire, USA ; Department of Biological Sciences, Dartmouth , Hanover, New Hampshire, USA.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Griswold