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Synthetic DNA/RNA Analogues Display Potent Antibiotic Activity

By BiotechDaily International staff writers
Posted on 29 Oct 2013
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Image: Scanning electron microscope image of A. baumannii, with maps of its genome (outer circle) and alien-island sequences (inner circle, red) (Photo courtesy of J. Carr, [US] Centers for Disease Control; T. Gianoulis and D. Massa, Yale University).
Image: Scanning electron microscope image of A. baumannii, with maps of its genome (outer circle) and alien-island sequences (inner circle, red) (Photo courtesy of J. Carr, [US] Centers for Disease Control; T. Gianoulis and D. Massa, Yale University).
Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs), which are synthetic DNA/RNA analogues that silence expression of specific genes, were found to inhibit the growth of Acinetobacter in vitro and in vivo.

Acinetobacter is frequently isolated in nosocomial infections and is especially prevalent in intensive care units with sporadic cases as well as epidemic and endemic occurrence. A. baumannii is a frequent cause of nosocomial pneumonia, especially of late-onset ventilator associated pneumonia. It can cause various other infections including skin and wound infections, bacteremia, and meningitis, while A. lwoffi is mostly responsible for the latter. A. baumannii can survive on the human skin or dry surfaces for weeks. Acinetobacter species are innately resistant to many classes of antibiotics, including penicillin, chloramphenicol, and often aminoglycosides.

Investigators at Oregon State University (Corvallis, OR, USA) sought to determine whether PPMOs targeted to essential genes in A. lwoffii and A. baumannii were active in vitro and in vivo. They evaluated PPMOs in vitro cultures using the minimum inhibitory concentration (MIC) of the drug and viability assays, and in vivo using mouse pulmonary infection models with intranasal PPMO treatment.

Results published in the October 14, 2013, online edition of the Journal of Infectious Diseases revealed that the most effective PPMO tested was (RXR)4-AcpP, which was targeted to the acpP gene. This PPMO reduced viability of A. lwoffii and A. baumannii by more than 1,000 colony-forming units per milliliter at five to eight times the MIC. Mice treated with (RXR)4-AcpP survived longer and had less inflammation and bacterial lung burden than mice treated with a scrambled-sequence PPMO or phosphate-buffered saline. Treatment could be delayed after infection and still increase survival.

“The mechanism that PPMOs use to kill bacteria is revolutionary,” said first author Dr. Bruce Geller, professor of microbiology at Oregon State University. “They can be synthesized to target almost any gene, and in that way avoid the development of antibiotic resistance and the negative impacts sometimes associated with broad-spectrum antibiotics.”

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Oregon State University



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