Conjugative plasmid transfer is limited by prophages but can be overcome by high conjugation rates

Abstract

Antibiotic resistance spread via plasmids is a serious threat to successful treatment and makes understanding plasmid transfer in nature crucial to preventing the global rise of antibiotic resistance. However, plasmid dynamics have so far neglected one omnipresent factor: active prophages (phages that are integrated into the bacterial genome), whose activation can kill co-occurring bacteria. To investigate how prophages influence the spread of a multi-drug resistant plasmid, we combined experiments and mathematical modelling. Using E. coli, prophage lambda and the plasmid Rp4 we find that prophages clearly limit the spread of conjugative plasmids. This effect was even more pronounced when we studied this interaction in a phage-friendly environment that favoured phage adsorption. Our empirically parameterized model reproduces experimental dynamics in some environments well, but fails to predict them in others, suggesting more complex interactions between plasmid and prophage infection dynamics. Varying phage and plasmid infection parameters over an empirically realistic range suggests that plasmids can overcome the negative impact of prophages through high conjugation rates. Overall, we find that the presence of prophages introduces an additional death rate for plasmid carriers, the magnitude of which is determined in non-trivial ways by the environment, the phage and the plasmid.

Ecological dynamics of plasmid transfer and persistence in microbial communities

“…Harrison et al [51] showed recurrent selective sweeps of phage resistance mutations can initially stabilise costly plasmids, but ultimately drove the loss of plasmids from populations of Pseudomonas fluorescens [51] . Similar results have been observed during prophage infection, where plasmid spread is limited due to an increased mortality rate in the plasmid carrying fraction of the population [52] . Some phages can also specifically target the conjugation machinery of plasmids, selecting against plasmid carriage resulting in the loss of the plasmid and hence the phage receptor, as a mechanism of phage resistance [53] .…”

“…The complexity of microbial communities will make it challenging to answer such questions, in part due to the diversity of hosts — differing in their ability to receive, maintain and disseminate plasmids — as well as the diversity of interspecies and multitrophic interactions that are present within natural communities. A combination of approaches including the use of more representative in vitro multispecies and multitrophic communities (such as 54 , 56 ), increased focus on theoretically modelling the effects of diversity and interspecies interactions (such as 52 , 65•• ), and observing the dynamics of plasmid transfer within natural microbiomes (such as [24] ) will all contribute to developing a deeper understanding of plasmid dynamics in complex communities.…”

Introduction: the secret lives of microbial mobile genetic elements

“…Conflicts and collaborations between MGEs also extend across MGE types. In a series of experiments extended and explored with deterministic modelling, Igler et al [43] investigate how conjugative plasmids and integrative prophages affect each other's transmission. Though neither the plasmid nor the phage used in their experiments (lambda and RP4) contained systems known to directly interfere with transfer, they found that prophages limited conjugative plasmid spread directly by killing recipients, and suggest that prophages may also inhibit plasmid entry.…”

Conjugative plasmid transfer is limited by prophages but can be overcome by high conjugation rates

“…Data accessibility. Data are available from the Dryad Digital Repository: https://doi.org/10.5061/dryad.s4mw6m972 [52]. Competing interests.…”