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Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance
Published on: May 2, 2018
Chromosomal resistance mutations facilitate acquisition of multidrug-resistant plasmids in Escherichia coli
Khadija-Siddiqa N Hanga1, Michael A Brockhurst1, Michael J Bottery1
1Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PT, UK.
Abstract:
Bacteria can gain multiple resistance mechanisms in a single step by the acquisition of multidrug-resistant (MDR) plasmids, but it is unclear how antibiotic selection during the acquisition of MDR plasmids affects the evolution of additional resistance mechanisms. Through conjugating separate extended-spectrum β-lactamase (ESBL)- and carbapenemase-producing MDR plasmids into plasmid-naive Escherichia coli hosts, we examine the effects of acquisition of a single plasmid or co-acquisition of multiple plasmids upon fitness costs, resistance and subsequent genomic adaptation. We show that acquisition of pOXA-48, encoding OXA-48 carbapenemase, is associated with highly variable fitness costs and levels of resistance to ertapenem in transconjugants independent of the presence of pLL35. This phenomenon was not observed during the acquisition of ESBL CTX-M-15-encoding pLL35 alone. Within a single growth cycle, transconjugants receiving pOXA-48 rapidly gained parallel mutations affecting the membrane porin OmpF, or its regulators OmpR or EnvZ. These chromosomal mutations were not compensatory for the fitness costs imposed by the plasmid, nor did they provide significant increases in resistance to carbapenems in the absence of the pOXA-48. Rather, they acted synergistically with the plasmid-encoded carbapenemase, which alone only provided marginal resistance, together providing high-level resistance to ertapenem. Such rapid evolutionary processes may play an important role in plasmid dynamics within environments with strong antibiotic selection for plasmid-encoded antimicrobial resistance genes (ARGs), particularly when these ARGs provide only marginal resistance.
Insights
Bacteria rapidly evolve higher antibiotic resistance when acquiring multidrug-resistant (MDR) plasmids. Even marginal resistance from plasmids drives rapid genomic changes, enhancing resistance in environments with strong antibiotic selection.
Area of Science:
- Microbiology
- Evolutionary Biology
- Genetics
Background:
- Multidrug-resistant (MDR) plasmids enable bacteria to acquire multiple resistance mechanisms simultaneously.
- The impact of antibiotic selection on the evolution of resistance during MDR plasmid acquisition remains poorly understood.
Purpose of the Study:
- To investigate how antibiotic selection influences genomic adaptation and resistance evolution following MDR plasmid acquisition in *Escherichia coli*.
- To examine the fitness costs, resistance levels, and subsequent genomic changes associated with single or multiple MDR plasmid acquisitions.
Main Methods:
- Conjugation of separate extended-spectrum *β*-lactamase (ESBL)- and carbapenemase-producing MDR plasmids into plasmid-naive *Escherichia coli*.
- Analysis of fitness costs, resistance profiles, and genomic mutations (e.g., in porins and their regulators) in transconjugants.
- Assessment of the synergistic effects of plasmid-encoded resistance and chromosomal mutations.
Main Results:
- Acquisition of the OXA-48 carbapenemase plasmid (pOXA-48) led to variable fitness costs and ertapenem resistance, unlike the ESBL plasmid (pLL35).
- Transconjugants with pOXA-48 rapidly acquired parallel chromosomal mutations in OmpF, OmpR, or EnvZ within one growth cycle.
- These mutations, while not compensatory for fitness costs, synergized with the plasmid-encoded carbapenemase to confer high-level ertapenem resistance.
Conclusions:
- Rapid genomic adaptation, driven by chromosomal mutations, can occur swiftly following MDR plasmid acquisition, especially under antibiotic selection.
- These evolutionary processes are crucial for plasmid dynamics in environments favoring antimicrobial resistance genes (ARGs), even those conferring only marginal resistance.
- The interplay between plasmid-borne ARGs and host chromosomal adaptations is a key factor in the emergence of high-level bacterial resistance.
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