title: Novel antimicrobial peptide-modified azithromycin-loaded liposomes against methicillin-resistantStaphylococcus aureus.
abstract: Infections caused by multidrug-resistant bacteria, such as methicillin-resistantStaphylococcus aureus(MRSA), have become a public threat; therefore, development of new antimicrobial drugs or strategies is urgently required. In this study, a new antibacterial peptide DP7-C (Chol-suc-VQWRIRVAVIRK-NH2) and DP7-C-modified azithromycin (AZT)-loaded liposomes (LPs) are developed for the treatment of MRSA infection, and it was found that DP7-C inserted into the LP lipid bilayer not only functioned as a carrier to encapsulate the antibiotic AZT but also synergized the antibacterial effect of the encapsulated AZT. In vitro assays showed that DP7-C-modified LPs possessed sustained drug release profile and immune regulatory effect and did not show obvious cytotoxicity in mammal cells, but they did not possess direct antibacterial activity in vitro. In vivo studies revealed that DP7-C-modified LPs did not exhibit obvious side effects or toxicity in mice but were able to significantly reduce the bacterial counts in an MRSA-infectious mouse model and possessed high antibacterial activity. In particular, DP7-C-modified AZT-loaded LPs showed more positive therapeutic effects than either DP7-C-modified blank LPs or nonmodified AZT-loaded LPs treatment alone. Molecular mechanism studies demonstrated that DP7-C formulations effectively upregulated the production of anti-inflammatory cytokines and chemokines without inducing harmful immune response, suggesting that DP7-C was synergistic with AZT against the bacterial infection by activating the innate immune response. Most importantly, although DP7-C activated the innate immune response, it did not possess direct antibacterial activity in vitro, indicating that DP7-C did not possess the potential to induce bacteria resistance. The findings indicate that DP7-C-modified AZT-loaded LPs developed in this study have a great potential required for the clinical treatment of MRSA infections.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Thyroid and Breast Surgery; Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Thyroid and Breast Surgery; Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Thyroid and Breast Surgery; Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Fengbo
authors.initials: F
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy.
authors.forename: Ke
authors.initials: K
authors.lastname: Men
authors.affiliation: Department of Thyroid and Breast Surgery; Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D017963:Azithromycin / Q000737:chemistry*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008051:Lipid Bilayers / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry*; D016106:Methicillin Resistance; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D010316:Particle Size; D010455:Peptides / Q000737:chemistry; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008051:Lipid Bilayers; D008081:Liposomes; D010455:Peptides; D017963:Azithromycin
keywords: DP7-C; MRSA infections; antimicrobial resistance; azithromycin; immune-regulation