Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 41, Issue 4, Pages 358-362Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijantimicag.2012.11.017
Keywords
Peptide nucleic acid (PNA); Brucella; Antibiotic resistance; Antisense; Murine macrophage
Funding
- Virginia-Maryland Regional College of Veterinary Medicine (Blacksburg, VA)
- National Institutes of Health (NIH) [5R03AI083735-02]
- National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services [HHSN272200900040C]
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Peptide nucleic acids (PNAs) are single-stranded, synthetic nucleic acid analogues containing a pseu-dopeptide backbone in place of the phosphodiester sugar-phosphate. When PNAs are covalently linked to cell-penetrating peptides (CPPs) they readily penetrate the bacterial cell envelope, inhibit expression of targeted genes and cause growth inhibition both of Gram-positive and Gram-negative bacteria. However, the effectiveness of PNAs against Brucella, a facultative intracellular bacterial pathogen, was unknown. The susceptibility of a virulent Brucella suis strain to a variety of PNAs was assessed in pure culture as well as in murine macrophages. The studies showed that some of the PNAs targeted to Brucella genes involved in DNA (polA, dnaG, gyrA), RNA (rpoB), cell envelope (asd), fatty acid (kdtA, acpP) and protein (tsf) synthesis inhibit the growth of B. suis in culture and in macrophages after 24 h of treatment. PNA treatment inhibited Brucella growth by interfering with gene expression in a sequence-specific and dose-dependent manner at micromolar concentrations. The most effective PNA in broth culture was that targeting polA at ca. 12 mu M. In contrast, in B. suis-infected macrophages, the most effective PNAs were those targeting asd and dnaG at 30 mu M; both of these PNAs had little inhibitory effect on Brucella in broth culture. The polA PNA that inhibits wild-type B. suis also inhibits the growth of wild-type Brucella melitensis 16M and Brucella abortus 2308 in culture. This study reveals the potential usefulness of antisense PNA constructs as novel therapeutic agents against intracellular Brucella. (c) 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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