Journal
NUCLEIC ACID THERAPEUTICS
Volume 22, Issue 5, Pages 323-334Publisher
MARY ANN LIEBERT INC
DOI: 10.1089/nat.2012.0370
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Funding
- European Commission Seventh framework NABATIVI project grant [223670]
- Danish Council for Independent Research/Medical Sciences
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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-beta ala or the H-(R-Ahx)(6)-beta ala peptide exhibited complete growth inhibition of P. aeruginosa strains PA01, PA14, and LESB58 at 1-2 mu M concentrations without any indication of bacterial membrane disruption (even at 20 mu M), 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 anti-bacterials for treatment of Pseudomonas infections.
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