title: Antisense growth inhibition of methicillin-resistant Staphylococcus aureus by locked nucleic acid conjugated with cell-penetrating peptide as a novel FtsZ inhibitor.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) infections are becoming increasingly difficult to treat, owing to acquired antibiotic resistance. The emergence and spread of MRSA limit therapeutic options and require new therapeutic strategies, including novel MRSA-active antibiotics. Filamentous temperature-sensitive protein Z (FtsZ) is a highly conserved bacterial tubulin homologue that is essential for controlling the bacterial cell division process in different species of S. aureus. We conjugated a locked nucleic acid (LNA) that targeted ftsZ mRNA with the peptide (KFF)3K, to generate peptide-LNA (PLNA). The present study aimed to investigate whether PLNA could be used as a novel antibacterial agent. PLNA787, the most active agent synthesized, exhibited promising inhibitory effects on four pathogenic S. aureus strains in vitro. PLNA787 inhibited bacterial growth and resolved lethal Mu50 infections in epithelial cell cultures. PLNA787 also improved the survival rates of Mu50-infected mice and was associated with reductions of bacterial titers in several tissue types. The inhibitory effects on ftsZ mRNA and FtsZ protein expression and inhibition of the bacterial cell division process are considered to be the major mechanisms of PLNA. PLNA787 demonstrated activity against MRSA infections in vitro and in vivo. Our findings suggest that ftsZ mRNA is a promising new target for developing novel antisense antibiotics.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Jingru
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Da
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Administrative Pharmacy and Pharmaceutical Information, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Huinan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Mingkai
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hou
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China xxluo3@fmmu.edu.cn.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Luo
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000494:pharmacology*; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009841:Oligonucleotides / Q000737:chemistry*; D013203:Staphylococcal Infections
chemical_list: D001426:Bacterial Proteins; D057846:Cell-Penetrating Peptides; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D009841:Oligonucleotides; C477371:locked nucleic acid