title: Potent antibacterial antisense peptide-peptide nucleic acid conjugates against Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa is an opportunistic pathogen causing severe infections in hospital settings, especially with immune compromised patients, and the increasing prevalence of multidrug resistant strains urges search for new drugs with novel mechanisms of action. In this study we introduce antisense peptide-peptide nucleic acid (PNA) conjugates as antibacterial agents against P. aeruginosa. We have designed and optimized antisense peptide-PNA conjugates targeting the translation initiation region of the ftsZ gene (an essential bacterial gene involved in cell division) or the acpP gene (an essential bacterial gene involved in fatty acid synthesis) of P. aeruginosa (PA01) and characterized these compounds according to their antimicrobial activity and mode of action. Four antisense PNA oligomers conjugated to the H-(R-Ahx-R)(4)-Ahx-βala or the H-(R-Ahx)(6)-βala peptide exhibited complete growth inhibition of P. aeruginosa strains PA01, PA14, and LESB58 at 1-2 μM concentrations without any indication of bacterial membrane disruption (even at 20 μM), and resulted in specific reduction of the targeted mRNA levels. One of the four compounds showed clear bactericidal activity while the other significantly reduced bacterial survival. These results open the possibility of development of antisense antibacterials for treatment of Pseudomonas infections.
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, Copenhagen N, Denmark.
authors.forename: Anubrata
authors.initials: A
authors.lastname: Ghosal
authors.forename: Peter E
authors.initials: PE
authors.lastname: Nielsen
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology*; D020135:Peptide Nucleic Acids / Q000378:metabolism / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D016376:Oligonucleotides, Antisense; D020135:Peptide Nucleic Acids