Biology subjects

Fruet, C.

Publications and source records attributed to Fruet, C..

5 recordsLinked to original sources

bioRxiv2026

Competition against the intestinal microbiota selects for pathoadaptive traits in ESBL E. coli

The intestinal tract is a reservoir for Extended-Spectrum {beta}-Lactamase (ESBL)-producing Escherichia coli. Asymptomatic gut colonization by these pathobionts represents a major risk for extraintestinal infections. Despite clinical relevance, the genetic basis of gut colonization by ESBL E. coli remains poorly understood. Here, we determined how the microbiota shapes the fitness landscape of diverse ESBL E. coli strains, defining the functional requirements for intestinal colonization. In microbiota-depleted hosts, colonization relies mostly on metabolic functions. In contrast, in mice harbouring a microbiota, pathoadaptive functions associated with adhesion and biofilm formation are dominant determinants of E. coli fitness, together with accessory virulence functions. Consistent with these observations, experimental evolution in mice reveals convergent adaptation of ESBL E. coli to the presence of a complex microbiota through enhanced adhesion. These findings establish the microbiota as a major ecological driver of pathoadaptation in antibiotic-resistant pathobionts.

microbiology↗

bioRxiv2026

Predicting host-pathogen interactions using a proteome-scale language model

ProteomeLM (Malbranke et al., 2025) is a proteome-scale language model trained on proteomes spanning the tree of life to reconstruct masked protein embeddings from proteome context within each species. Its attention coefficients capture protein-protein interactions without supervision. Here, we show that this capability extends to cross-species host-pathogen interactions (HPI) across ten human pathogen taxa spanning viruses and bacteria, and can be further improved with lightweight fine-tuning. We introduce ProteomeLM-HPI, a parameter-efficient adaptation via LoRA, trained on concatenated host-pathogen proteomes to reconstruct masked pathogen embeddings from host context. ProteomeLM-HPI involves two key design choices: asymmetric masking (pathogen-heavy masking) and blocked self-attention. Systematic ablations show that both choices contribute. To assess generalization, we introduce a strict cross-species benchmark enforcing pathogen-level hold-out and 40% sequence-identity filtering. On this benchmark, Proteome-HPI improves AUC on 9 out of 10 unseen pathogens.

bioinformatics↗

bioRxiv2025

Environment heterogeneity creates fast amplifiers of natural selection in graph-structured populations

Complex spatial structure, with partially isolated subpopulations, and environment heterogeneity, such as gradients in nutrients, oxygen, and drugs, both shape the evolution of natural populations. We investigate the impact of environment heterogeneity on mutant fixation in spatially structured populations with demes on the nodes of a graph. When migrations between demes are frequent, we find that environment heterogeneity can amplify natural selection and simultaneously accelerate mutant fixation and extinction, thereby fostering the quick fixation of beneficial mutants. We demonstrate this effect in the star graph, and more strongly in the line graph. We show that amplification requires mutants to have a stronger fitness advantage in demes with stronger migration outflow, and that this condition allows amplification in more general graphs. As a baseline, we consider circulation graphs, where migration inflow and outflow are equal in each deme. In this case, environment heterogeneity has no impact to first order, but increases the fixation probability of beneficial mutants to second order. Finally, when migrations between demes are rare, we show that environment heterogeneity can also foster amplification of selection, by allowing demes with sufficient mutant advantage to become refugia for mutants.

evolutionary biology↗

bioRxiv2024

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↗

bioRxiv2023

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↗