title: A peptide-morpholino oligomer conjugate targeting Staphylococcus aureus gyrA mRNA improves healing in an infected mouse cutaneous wound model.
abstract: Management of skin wound infections presents a serious problem in the clinic, in the community, and in both civilian and military clinical treatment centers. Staphylococcus aureus is one of the most common microbial pathogens in cutaneous wounds. Peptide-morpholino oligomer (PMO) conjugates targeted to S. aureus gyrase A mRNA have shown the ability to reduce bacterial viability by direct site-specific mRNA cleavage via RNase P. As a treatment, these conjugates have the added advantages of not being susceptible to resistance due to genetic mutations and are effective against drug resistant strains. While this strategy has proven effective in liquid culture, it has yet to be evaluated in an animal model of infected surface wounds. In the present study, we combined PMO conjugates with a thermoresponsive gel delivery system to treat full-thickness mouse cutaneous wounds infected with S. aureus. Wounds treated with a single dose of PMO conjugate displayed improved healing that was associated with increased epithelialization, reduced bacterial load, and increased matrix deposition. Taken together, our findings demonstrate the efficacy and flexibility of the PMO conjugate drug delivery system and make it an attractive and novel topical antimicrobial agent.
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Sawyer
authors.forename: Donna
authors.initials: D
authors.lastname: Wesolowski
authors.forename: Neeru
authors.initials: N
authors.lastname: Gandotra
authors.forename: Alexander
authors.initials: A
authors.lastname: Stojadinovic
authors.forename: Mina
authors.initials: M
authors.lastname: Izadjoo
authors.forename: Sidney
authors.initials: S
authors.lastname: Altman
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D027081:DNA Gyrase / Q000235:genetics*; D016503:Drug Delivery Systems; D051379:Mice; D008810:Mice, Inbred C57BL; D060172:Morpholinos / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000473:pathology; D013211:Staphylococcus aureus; D014945:Wound Healing / Q000187:drug effects; D014946:Wound Infection / Q000473:pathology / Q000628:therapy*
chemical_list: D000900:Anti-Bacterial Agents; D060172:Morpholinos; D010455:Peptides; D012333:RNA, Messenger; D027081:DNA Gyrase
keywords: PMOs; RNase P; Skin wounds; Staphylococcus aureus