title: Conjugation Approach To Produce a Staphylococcus aureus Synbody with Activity in Serum.
abstract: Synbodies show promise as a new class of synthetic antibiotics. Here, we explore improvements in their activity and production through conjugation chemistry. Maleimide conjugation is a widely used conjugation strategy due to its high yield, selectivity, and low cost. We used this strategy to conjugate two antibacterial peptides to produce a bivalent antibacterial peptide, called a synbody that has bactericidal activity against methicillin resistant Staphylococcus aureus (MRSA). The synbody was prepared by conjugation of a partially d-amino acid substituted synthetic antibacterial peptide to a bis-maleimide scaffold. The synbody slowly degrades in serum, but also undergoes exchange reactions with other serum proteins, such as albumin. Therefore, we hydrolyzed the thiosuccinimide ring using a mild hydrolysis protocol to produce a new synbody with similar bactericidal activity. The synbody was now resistant to exchange reactions and maintained bactericidal activity in serum for 2 h. This work demonstrates that low-cost maleimide coupling can be used to produce antibacterial peptide conjugates with activity in serum.
authors.affiliation: Center for Innovation in Medicine, Biodesign Institute, and ‡School of Life Sciences, Arizona State University , Tempe, Arizona 85287, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: Lainson
authors.affiliation: Center for Innovation in Medicine, Biodesign Institute, and ‡School of Life Sciences, Arizona State University , Tempe, Arizona 85287, United States.
authors.forename: Mariana Ferrer
authors.initials: MF
authors.lastname: Fuenmayor
authors.affiliation: Center for Innovation in Medicine, Biodesign Institute, and ‡School of Life Sciences, Arizona State University , Tempe, Arizona 85287, United States.
authors.forename: Stephen Albert
authors.initials: SA
authors.lastname: Johnston
authors.affiliation: Center for Innovation in Medicine, Biodesign Institute, and ‡School of Life Sciences, Arizona State University , Tempe, Arizona 85287, United States.
authors.forename: Chris W
authors.initials: CW
authors.lastname: Diehnelt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006868:Hydrolysis; D008301:Maleimides / Q000737:chemistry; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D010455:Peptides / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D013388:Succinimides / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D008301:Maleimides; D010455:Peptides; D013388:Succinimides; D013438:Sulfhydryl Compounds; C032620:succinimide; C043592:maleimide