Antibiotic heteroresistance generated by multi-copy plasmids

Hernandez‐Beltran

Siri‐Jégousse

et al. 2022

Preprint

Self Cite

Plasmids are extra-chromosomal genetic elements that encode a wide variety of phenotypes and can be maintained in bacterial populations through vertical and horizontal transmission, thus increasing bacterial adaptation to hostile environmental conditions like those imposed by antimicrobial substances. To circumvent the segregational instability resulting from randomly distributing plasmids between daughter cells upon division, non-transmissible plasmids tend to be carried in multiple copies per cell, with the added benefit of exhibiting increased gene dosage. But carrying multiple copies also results in a high metabolic burden to the bacterial host, therefore reducing the overall fitness of the population. This trade-off poses an existential question for plasmids: What is the optimal plasmid copy number? In this manuscript, we address this question using a combination of population genetics modeling with microbiology experiments consisting of Escherichia coli K12 bearing a multi-copy plasmid encoding for bla TEM-1 , a gene conferring resistance to β -lactam antibiotics. We postulate and analyze a Wright-Fisher model to evaluate the interaction between selective pressure, the number of plasmid copies carried by each cell, and the energetic cost associated with plasmid bearing. By numerically determining the optimal plasmid copy number for constant and fluctuating selection regimes, we show that the stability of multi-copy plasmids is maximized at intermediate plasmid copy numbers. We conclude by arguing that plasmid copy number is a highly optimized evolutionary trait that depends on the rate of environmental fluctuation and balances the benefit between increased stability in the absence of selection with the burden associated with carrying multiple copies of the plasmid.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Model Parametrizationmentioning

confidence: 99%

Section: /29mentioning

confidence: 99%

See 2 more Smart Citations

Segregational instability of multicopy plasmids: a population genetics approach

Hernandez‐Beltran

Siri‐Jégousse

et al. 2022

Preprint

Self Cite

“…43 Besides a reduction in segregational instability, increasing the number of plasmids each cell carries also results in an increase in gene dosage 44,45 and expression variability of plasmid-encoded genes. 25,46 For this reason, plasmid control in wild-type bacteria is a tightly regulated process 47 that depends on the environment and the host's genetics. 8 Precise PCN control is also an important feature of synthetic genetic circuits that use plasmids as vectors for the production of recombinant substances.…”

Section: /29mentioning

confidence: 99%

Plasmid stability in fluctuating environments: population genetics of multi-copy plasmids

Hernandez‐Beltran¹,

Siri‐Jégousse³

et al. 2022

Preprint

Plasmids are extra-chromosomal genetic elements that encode a wide variety of phenotypes and can be maintained in bacterial populations through vertical and horizontal transmission, thus increasing bacterial adaptation to hostile environmental conditions like those imposed by antimicrobial substances. To circumvent the segregational instability resulting from randomly distributing plasmids between daughter cells upon division, non-transmissible plasmids tend to be carried in multiple copies per cell, which also results in a metabolic burden to the bacterial host, therefore reducing the overall fitness. This trade-off poses an existential question for plasmids: What is the optimal plasmid copy number? We address this question using a combination of population genetics modeling with microbiology experiments consisting of Escherichia coli K12 bearing a multi-copy plasmid encoding for blaTEM-1, a gene conferring resistance to b-lactam antibiotics. We use a Wright-Fisher model to evaluate the interaction between the above mentioned opposing forces. By numerically determining the optimal plasmid copy number for constant and fluctuating selection regimes, we conclude that plasmid copy number is an optimized evolutionary trait that depends on the rate of environmental fluctuation and balances the benefit between increased stability in the absence of selection with the burden associated with carrying multiple copies of the plasmid.

Segregational instability of multicopy plasmids: A population genetics approach

Hernandez‐Beltran

Siri‐Jégousse

et al. 2022

Ecology and Evolution

Self Cite

Plasmids are extra‐chromosomal genetic elements that encode a wide variety of phenotypes and can be maintained in bacterial populations through vertical and horizontal transmission, thus increasing bacterial adaptation to hostile environmental conditions like those imposed by antimicrobial substances. To circumvent the segregational instability resulting from randomly distributing plasmids between daughter cells upon division, nontransmissible plasmids tend to be carried in multiple copies per cell, with the added benefit of exhibiting increased gene dosage and resistance levels. But carrying multiple copies also results in a high metabolic burden to the bacterial host, therefore reducing the overall fitness of the population. This trade‐off poses an existential question for plasmids: What is the optimal plasmid copy number? In this manuscript, we address this question by postulating and analyzing a population genetics model to evaluate the interaction between selective pressure, the number of plasmid copies carried by each cell, and the metabolic burden associated with plasmid bearing in the absence of selection for plasmid‐encoded traits. Parameter values of the model were estimated experimentally using Escherichia coli K12 carrying a multicopy plasmid encoding for a fluorescent protein and bla TEM‐1 , a gene conferring resistance to β ‐lactam antibiotics. By numerically determining the optimal plasmid copy number for constant and fluctuating selection regimes, we show that plasmid copy number is a highly optimized evolutionary trait that depends on the rate of environmental fluctuation and balances the benefit between increased stability in the absence of selection with the burden associated with carrying multiple copies of the plasmid.