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Antibiotic resistance has become a serious public health issue, fundamentally undermining the treatment of bacterial infections. Could a new generation of antimicrobial agents be on their way? A study published today in the Journal of Infectious Diseases by research groups in Oregon State University, the University of Texas, Southwestern Medical Center, and Sarepta, Inc. in Oregon suggests a promising way forward.

These groups have used antisense strategies to target two strains of Acinetobacter, a group of bacteria which has developed multi-drug resistance and is causing global problems in arenas such as hospitals and among military personnel in the Middle East. The antisense constructs used are termed peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO), a synthetic analogue of DNA or RNA conjugated to peptide. They differ from antibiotics in that they target the bacterial genes directly. Previous studies had suggested the potential effectiveness of PPMOs. For example, in Burkholderia cepacia complex (Bcc), PPMOs against acpP, an acyl carrier protein essential for growth, were shown to be bactericidal both in vitro and in an in vivo mouse model of chronic granulomatous disease. This was promising as many Bcc strains are antibiotic resistant and are a main cause of morbidity and mortality in chronic granulomatous disease and cystic fibrosis patients. Other studies had also shown that the potency of PPMOs was linked to the peptide composition. In the current study, in vivo animal studies were carried out to determine the effectiveness of PPMOs against A. baumannii, a very dangerous Acinetobacter strain. It was shown that PPMOs had a powerful bactericidal effect that outstripped conventional antibiotics like ampicillin, and was comparable to the strongest available antibiotics. Effectiveness was sustained against antibiotic-resistant bacteria.

It is still early days in the story of PPMO as a potential therapy for bacterial infection. While the basic PMO has been tested in humans and found to be safe, the peptide-conjugated form has yet to be tested. Further research and extensive clinical trials would be required before they could be considered for use as therapeutic agents in humans. However, the indications are promising that antisense strategies targeted at the bacterial genes, rather than attempts to modify existing therapies, may one day help overcome the serious problem of antibiotic resistance.

Sources

GELLER, B.L. et al., 2013. Gene-Silencing Antisense Oligomers Inhibit Acinetobacter Growth In Vitro and In Vivo. Journal of Infectious Diseases, October 2013

GREENBERG, D.E. et al., 2010. Antisense phosphorodiamidate morpholino oligomers targeted to an essential gene inhibit Burkholderia cepacia complex. Journal of Infectious Diseases, 201(12), pp. 1822-1830

MELLBYE, B.L. et al., 2009. Variations in amino acid composition of antisense peptide-phosphorodiamidate morpholino oligomer affect potency against Escherichia coli in vitro and in vivo. Antimicrobial Agents and Chemotherapy, 53(2), pp. 525-530

WOODFORD, N. and WAREHAM, D.W., 2009. Tackling antibiotic resistance: a dose of common antisense? The Journal of Antimicrobial chemotherapy, 63(2), pp. 225-229

Oregon State University. "Beyond antibiotics: 'PPMOs' offer new approach to bacterial infection, other diseases." ScienceDaily, 15 Oct. 2013. [Accessed 15 Oct. 2013]