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Antimicrobial Agents and Chemotherapy, March 2007, p. 805-811, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.00709-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of Gene Expression and Growth by Antisense Peptide Nucleic Acids in a Multiresistant ß-Lactamase-Producing Klebsiella pneumoniae Strain{triangledown}

Prathiba Kurupati,1 Kevin Shyong Wei Tan,1 Gamini Kumarasinghe,2 and Chit Laa Poh1*

Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117597,1 Department of Laboratory Medicine, National University Hospital, Kent Ridge, Singapore 119074, Singapore2

Received 8 June 2006/ Returned for modification 14 August 2006/ Accepted 1 December 2006

Klebsiella pneumoniae causes common and severe hospital- and community-acquired infections with a high incidence of multidrug resistance. The emergence and spread of ß-lactamase-producing K. pneumoniae strains highlight the need to develop new therapeutic strategies. In this study, we developed antisense peptide nucleic acids (PNAs) conjugated to the (KFF)3K peptide and investigated whether they could mediate gene-specific antisense effects in K. pneumoniae. No outer membrane permeabilization was observed with antisense PNAs when used alone. Antisense peptide-PNAs targeted at two essential genes, gyrA and ompA, were found to be growth inhibitory at concentrations of 20 µM and 40 µM, respectively. Mismatched antisense peptide-PNAs with sequence variations of the gyrA and ompA genes when used as controls were not growth inhibitory. Bactericidal effects exerted by peptide-anti-gyrA PNA and peptide-anti-ompA PNA on cells were observed within 6 h of treatment. The antisense peptide-PNAs specifically inhibited expression of DNA gyrase subunit A and OmpA from the respective targeted genes in a dose-dependent manner. Both antisense peptide-PNAs cured IMR90 cell cultures that were infected with K. pneumoniae (104 CFU) in a dose-dependent manner without any noticeable toxicity to the human cells.

* Corresponding author. Mailing address: Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Block MD4, 5 Science Drive 2, Singapore 117597, Singapore. Phone: 65 6874 3674. Fax: 65 6776 6872. E-mail: micpohcl{at}nus.edu.sg.

{triangledown} Published ahead of print on 11 December 2006.

Antimicrobial Agents and Chemotherapy, March 2007, p. 805-811, Vol. 51, No. 3
0066-4804/07/$08.00+0     doi:10.1128/AAC.00709-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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