Engineered Phagemids for Nonlytic, Targeted Antibacterial Therapies

The increasing incidence of antibiotic-resistant bacterial infections is creating a global public health threat. Because conventional antibiotic drug discovery has failed to keep pace with the rise of resistance, a growing need exists to develop novel antibacterial methodologies. Replication-compete...

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Bibliographic Details
Published inNano letters Vol. 15; no. 7; pp. 4806 - 4811
Main Authors Krom, Russell J, Bhargava, Prerna, Lobritz, Michael A, Collins, James J
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 08.07.2015
Subjects
Animals
Anti-Bacterial Agents - metabolism
Antimicrobial Cationic Peptides - genetics
Bacteriophages - genetics
Escherichia coli - physiology
Escherichia coli Infections - complications
Genetic Engineering
Genetic Therapy
Humans
Mice
Mice, Inbred C57BL
Peritonitis - genetics
Peritonitis - microbiology
Peritonitis - therapy
Plasmids - genetics
Plasmids - therapeutic use
Toxins, Biological - genetics
synthetic gene networks
targeted bacterial killing
bacterial toxins
bacteriophage resistance
phagemids
Antimicrobial peptides
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Summary:The increasing incidence of antibiotic-resistant bacterial infections is creating a global public health threat. Because conventional antibiotic drug discovery has failed to keep pace with the rise of resistance, a growing need exists to develop novel antibacterial methodologies. Replication-competent bacteriophages have been utilized in a limited fashion to treat bacterial infections. However, this approach can result in the release of harmful endotoxins, leading to untoward side effects. Here, we engineer bacterial phagemids to express antimicrobial peptides (AMPs) and protein toxins that disrupt intracellular processes, leading to rapid, nonlytic bacterial death. We show that this approach is highly modular, enabling one to readily alter the number and type of AMPs and toxins encoded by the phagemids. Furthermore, we demonstrate the effectiveness of engineered phagemids in an in vivo murine peritonitis infection model. This work shows that targeted, engineered phagemid therapy can serve as a viable, nonantibiotic means to treat bacterial infections, while avoiding the health issues inherent to lytic and replicative bacteriophage use.
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ISSN:1530-6984
1530-6992
DOI:10.1021/acs.nanolett.5b01943