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Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance
Published on: May 2, 2018
Bacterial death comes full circle: targeting plasmid replication in drug-resistant bacteria
Johna C B DeNap1, Paul J Hergenrother
1Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Abstract:
It is now common for bacterial infections to resist the preferred antibiotic treatment. In particular, hospital-acquired infections that are refractory to multiple antibiotics and ultimately result in death of the patient are prevalent. Many of the bacteria causing these infections have become resistant to antibiotics through the process of lateral gene transfer, with the newly acquired genes encoding a variety of resistance-mediating proteins. These foreign genes often enter the bacteria on plasmids, which are small, circular, extrachromosomal pieces of DNA. This plasmid-encoded resistance has been observed for virtually all classes of antibiotics and in a wide variety of Gram-positive and Gram-negative organisms; many antibiotics are no longer effective due to such plasmid-encoded resistance. The systematic removal of these resistance-mediating plasmids from the bacteria would re-sensitize bacteria to standard antibiotics. As such, plasmids offer novel targets that have heretofore been unexploited clinically. This Perspective details the role of plasmids in multi-drug resistant bacteria, the mechanisms used by plasmids to control their replication, and the potential for small molecules to disrupt plasmid replication and re-sensitize bacteria to antibiotics. An emphasis is placed on plasmid replication that is mediated by small counter-transcript RNAs, and the "plasmid addiction" systems that employ toxins and antitoxins.
Insights
Antibiotic resistance is a growing threat, often driven by plasmids carrying resistance genes. Targeting these plasmids could restore antibiotic effectiveness against dangerous bacterial infections.
Area of Science:
- Microbiology
- Molecular Biology
- Genetics
Background:
- Bacterial infections frequently exhibit antibiotic resistance, particularly hospital-acquired infections, leading to high mortality rates.
- Multi-drug resistance in bacteria is often mediated by genes acquired through lateral gene transfer, frequently located on plasmids.
Purpose of the Study:
- To explore the role of plasmids in bacterial multi-drug resistance.
- To detail plasmid replication mechanisms and potential therapeutic targets.
- To investigate the disruption of plasmid replication for resensitizing bacteria to antibiotics.
Main Methods:
- Review of current literature on plasmid biology and antibiotic resistance.
- Analysis of plasmid replication control mechanisms, including counter-transcript RNAs and addiction systems.
- Discussion of small molecule-based strategies to target plasmid replication.
Main Results:
- Plasmids are a significant factor in the spread of antibiotic resistance across diverse bacterial species.
- Plasmid replication is regulated by sophisticated systems, including RNA molecules and toxin-antitoxin pairs.
- Disrupting these plasmid-specific mechanisms offers a novel therapeutic avenue.
Conclusions:
- Plasmids are critical drivers of multi-drug resistant bacterial infections.
- Targeting plasmid replication and maintenance represents a promising strategy to combat antibiotic resistance.
- Small molecules interfering with plasmid addiction systems or replication could restore antibiotic efficacy.
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