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Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance
Published on: May 2, 2018
Plasmid interference for curing antibiotic resistance plasmids in vivo
Muhammad Kamruzzaman1, Shereen Shoma1, Christopher M Thomas2
1Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, The University of Sydney, Westmead, New South Wales, Australia.
Abstract:
Antibiotic resistance increases the likelihood of death from infection by common pathogens such as Escherichia coli and Klebsiella pneumoniae in developed and developing countries alike. Most important modern antibiotic resistance genes spread between such species on self-transmissible (conjugative) plasmids. These plasmids are traditionally grouped on the basis of replicon incompatibility (Inc), which prevents coexistence of related plasmids in the same cell. These plasmids also use post-segregational killing ('addiction') systems, which poison any bacterial cells that lose the addictive plasmid, to guarantee their own survival. This study demonstrates that plasmid incompatibilities and addiction systems can be exploited to achieve the safe and complete eradication of antibiotic resistance from bacteria in vitro and in the mouse gut. Conjugative 'interference plasmids' were constructed by specifically deleting toxin and antibiotic resistance genes from target plasmids. These interference plasmids efficiently cured the corresponding antibiotic resistant target plasmid from different Enterobacteriaceae in vitro and restored antibiotic susceptibility in vivo to all bacterial populations into which plasmid-mediated resistance had spread. This approach might allow eradication of emergent or established populations of resistance plasmids in individuals at risk of severe sepsis, enabling subsequent use of less toxic and/or more effective antibiotics than would otherwise be possible, if sepsis develops. The generalisability of this approach and its potential applications in bioremediation of animal and environmental microbiomes should now be systematically explored.
Insights
Researchers developed a novel method to eliminate antibiotic resistance genes from bacteria using engineered
Area of Science:
- Microbiology
- Molecular Biology
- Genetics
Background:
- Antibiotic resistance is a growing global health threat, increasing mortality from common bacterial infections.
- Antibiotic resistance genes frequently spread via conjugative plasmids within and between bacterial species.
- Plasmids utilize incompatibility (Inc) and addiction systems to ensure their persistence within bacterial populations.
Purpose of the Study:
- To investigate the potential of exploiting plasmid incompatibility and addiction systems for antibiotic resistance eradication.
- To develop and test 'interference plasmids' capable of eliminating antibiotic resistance plasmids from bacteria.
Main Methods:
- Engineered conjugative plasmids ('interference plasmids') by removing toxin and antibiotic resistance genes from target plasmids.
- Tested the efficacy of interference plasmids in curing antibiotic resistance plasmids from Enterobacteriaceae in vitro.
- Evaluated the restoration of antibiotic susceptibility in vivo using a mouse gut model.
Main Results:
- Interference plasmids successfully and completely eradicated target antibiotic resistance plasmids from various Enterobacteriaceae strains in vitro.
- Treatment with interference plasmids restored antibiotic susceptibility in bacterial populations in a mouse gut model.
- Demonstrated the potential for safe and complete removal of antibiotic resistance.
Conclusions:
- Exploiting plasmid incompatibility and addiction systems offers a promising strategy for eradicating antibiotic resistance.
- This approach could be valuable for treating individuals at risk of sepsis and for bioremediation applications.
- Further research is warranted to explore the generalizability and applications of this method in diverse microbiomes.
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