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Fruet, C.

Publications and source records attributed to Fruet, C..

2 recordsLinked to original sources

Spatial structure facilitates evolutionary rescue by cost-free drug resistance

Bacterial populations often have complex spatial structures, which can impact their evolution. Here, we study how spatial structure affects the evolution of antibiotic resistance in a bacterial population. We consider a minimal model of spatially structured populations where all demes (i.e., subpopulations) are identical and connected to each other by identical migration rates. We show that spatial structure can facilitate the survival of a bacterial population to antibiotic treatment, starting from a sensitive inoculum. Specifically, the bacterial population can be rescued if antibiotic resistant mutants appear and are present when drug is added, and spatial structure can impact the fate of these mutants and the probability that they are present. Indeed, the probability of fixation of neutral or deleterious mutations providing drug resistance is increased in smaller populations. This promotes local fixation of resistant mutants in the structured population, which facilitates evolutionary rescue by drug resistance in the rare mutation regime. Once the population is rescued by resistance, migrations allow resistant mutants to spread in all demes. Our main result that spatial structure facilitates evolutionary rescue by antibiotic resistance extends to more complex spatial structures, and to the case where there are resistant mutants in the inoculum. Author SummaryAntibiotic resistance is a major challenge, since bacteria tend to adapt to the drugs they are subjected to. Understanding what conditions facilitate or hinder the appearance and spread of resistance in a bacterial population is thus of strong interest. Most natural microbial populations have complex spatial structures. This includes host-associated microbiota, such as the gut microbiota. Here, we show that spatial structure can facilitate the survival of a bacterial population to antibiotic treatment, by promoting the presence of resistant bacteria. Indeed, neutral or deleterious mutants giving resistance can take over small populations more easily than large ones, thanks to the increased importance of fluctuations in small populations. Resistant mutants can then spread to the whole structured population. Thus, population spatial structure can be a source of antibiotic treatment failure. This effect of spatial structure is generic and does not require environment heterogeneity.

biophysics↗

A computational model for lipid-anchored polysaccharide export by the outer-membrane protein GfcD

Many bacteria are protected by different types of polysaccharide capsules, structures formed of long repetitive glycan chains that are sometimes free and sometimes anchored to the outer membrane via lipid tails. One type, called group 4 capsule, results from expression of the gfcABCDE-etp-etk operon in Escherichia coli. Of the proteins encoded in this operon, GfcE is thought to provide the export pore for free polysaccharide chains, but none of the proteins has been implicated in the export of chains carrying a lipid anchor. For this function, GfcD has been a focus of attention as the only outer-membrane {beta}-barrel encoded in the operon. AlphaFold predicts two {beta}-barrel domains in GfcD, a canonical N-terminal one of 12 strands and an unusual C-terminal one of 13 strands, which features a large lateral aperture between strands {beta}1 and {beta}13. This immediately suggests a lateral exit gate for hydrophobic molecules into the membrane, analogous to the one proposed for the lipopolysaccharide export pore LptD. Here, we report an unsteered molecular dynamics study of GfcD embedded in the bacterial outer membrane, with the common polysaccharide anchor, lipid A, inserted in the pore of the C-terminal barrel. Our results show that the lateral aperture does not collapse during simulations, that membrane lipids nevertheless do not penetrate the barrel, but that the lipid chains of the lipid A molecule readily exit into the membrane. Statement of SignificanceDespite the essential role polysaccharide capsules play in the resilience of bacteria to hostile environments, many aspects of their biogenesis are still poorly understood. One aspect concerns the export of capsular polysaccharides carrying a lipid anchor, for which even the proteins mediating the process are unknown. Here we propose that one of the largest families of {beta}-barrel proteins in the bacterial outer membrane is a key agent of this process and show by biophysical simulation that it allows the exit of lipid anchors into the membrane through a lateral opening. More generally, our model illuminates the lateral exit mechanisms proposed for the export of hydrophobic macromolecules into the bacterial outer membrane. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/565983v1_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@9b2feorg.highwire.dtl.DTLVardef@c668b2org.highwire.dtl.DTLVardef@386b8org.highwire.dtl.DTLVardef@181c418_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗