Biology subjects

Baudry, J.

Publications and source records attributed to Baudry, J..

5 recordsLinked to original sources

bioRxiv2020

Structure based virtual screening identifies novel competitive inhibitors for the sialoglycan binding protein Hsa

Infective endocarditis (IE) is a cardiovascular disease often caused by bacteria of the viridans group of streptococci, which includes Streptococcus gordonii and Streptococcus sanguinis. Previous research has found that a serine-rich repeat (SRR) proteins on the S. gordonii bacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialyated glycans displayed on human platelets. Despite its important role in disease progression, there are currently no anti-adhesive drugs available on the market. Here, we performed structure-based virtual screening using an ensemble docking approach followed by consensus scoring to identify novel inhibitors against the sialoglycan binding domain of the SRR adhesin protein Hsa from the S. gordonii strain DL1. In silico cross screening against the glycan binding domains of closely related SRR proteins from five other S. gordonii or S. sanguinis strains was also performed to further reduce false positives. Using our in silico screening strategy we successfully predicted nine compounds which were able to displace the native ligand (sialyl-T antigen) in an in vitro assay and bind competitively to adhesin protein Hsa ([~]20% hit rate).

microbiology↗

bioRxiv2020

Tree diversity and the temporal stability of mountain forest productivity: testing the effect of species composition, through asynchrony and overyielding

Climate change modifies ecosystem processes directly through its effect on environmental conditions, but also indirectly by changing community composition. Theoretical studies and grassland experiments suggest that diversity may increase and stabilize communities productivity over time. Few recent studies on forest ecosystems suggested the same pattern but with a larger variability between the results. In this paper, we aimed to test stabilizing diversity effect for two kinds of mixtures (Fagus sylvatica - Quercus pubescens and Fagus sylvatica - Abies alba), and to assess how climate may affect the patterns. We used tree ring data from forest plots distributed along a latitudinal gradient across French Alps. We found that diversity effect on stability in productivity varies with stand composition. Most beech-fir stands showed a greater stability in productivity over time than monocultures, while beech-oak stands showed a less stable productivity. Considering non-additive effects, no significant trends were found, regardless the type of mixed stands considered. We further highlighted that these patterns could be partially explained by asynchrony between species responses to annual climatic conditions (notably to variation in temperature or precipitation), overyielding, and climatic conditions. We also showed that the intensity of the diversity effect on stability varies along the ecological gradient, consistently with the stress gradient hypothesis for beech-oak forests, but not for beech-fir forests. This study showed the importance of the species identity on the relationships between diversity, climate and stability of forest productivity. Better depicting diversity and composition effects on forest ecosystem functioning appears to be crucial for forest managers to promote forest adaptation and maintain timber resource in the context of on-going climate change.

ecology↗

bioRxiv2019

Selectivity and engineering of the sialoglycan-binding spectrum in Siglec-like adhesins

The Siglec-like Serine-Rich Repeat (SRR) adhesins mediate bacterial attachment to mammalian hosts via sialoglycan receptors. Here, we combine structural, computational, biochemical, and phylogenetic approaches to elucidate the determinants of the sialoglycan-binding spectrum across the family of Siglec-like SRR adhesins. We further identified mutable positions that disproportionately affect sialoglycan selectivity, as demonstrated by increases in binding to alternative ligands of 2- to 3-orders of magnitude. Biologically, these studies highlight how bacteria nimbly modulate the receptor interaction during coevolution of host and pathogen. These studies additionally created binding proteins specific for sialyl-T antigen or 6S-sialyl LewisX that can recognize glycosylation of human plasma proteins. The engineered binding proteins can facilitate the characterization of normal cellular glycan modifications or may be used as diagnostic tools in disease states with altered glycosylation.\n\nSignificanceThe ability of bacteria to bind selectively to host receptors underlies both commensalism and pathogenesis. Here, we identify the molecular basis for receptor selectivity in streptococci that bind to sialoglycan receptors. This revealed how to convert these adhesins into selective probes that measure triand tetrasacharides within the context of larger glycosylations. These probes that can be used in a laboratory with no specialized equipment and can be used to address biological questions relating to sialoglycan-dependent signaling and adhesion.

biochemistry↗

bioRxiv2019

Interdimer zipping in the chemoreceptor signaling domain revealed by molecular dynamics simulations

Chemoreceptors are principal components of the bacterial sensory system that modulates cellular motility. They detect changes in the environment and transmit information to CheA histidine kinase, which ultimately controls cellular flagellar motors. The prototypical Tsr chemoreceptor in E. coli is a homodimer containing two principal functional modules: (i) a periplasmic ligand-binding domain and (ii) a cytoplasmic signaling domain. Chemoreceptor dimers are arranged into a trimer of dimers at the tip of the signaling domain comprising a minimal physical unit essential for enhancing the CheA activity several hundredfold. Trimers of dimers are arranged into highly ordered hexagon arrays at the cell pole; however, the mechanism underlying the trimer-of-dimer and higher order array formation remains unclear. Furthermore, molecular mechanisms of signal transduction that are likely to involve inter-dimer interactions are not fully understood. Here we apply all-atom, microsecond-time scale molecular dynamics simulations of the Tsr trimer of dimers atomic model in order to obtain further insight into potential interactions within the chemoreceptor signaling unit. We show extensive interactions between homodimers at the hairpin tip of the signaling domain, where strong hydrophobic interactions maintain binding. A subsequent zipping of homodimers is facilitated by electrostatic interactions, in particular by polar solvation energy and salt bridges that stabilize the final compact structure, which extends beyond the kinase interacting subdomain. Our study provides evidence that interdimer interactions within the chemoreceptor signaling domain are more complex than previously thought.

biophysics↗

bioRxiv2019

Metabolic Cost of Rapid Adaptation of Single Yeast Cells Under Unforeseen Challenge

Cells can rapidly adapt to changing environments through non-genetic processes; however, the metabolic cost of such adaptation has never been considered. Here we demonstrate metabolic coupling in a remarkable, rapid adaptation process (10-3cells/hour) by simultaneously measuring metabolism and division of thousands of individual Saccharomyces cerevisiae cells using a droplet microfluidic system. Following a severe challenge, most cells, while not dividing, continue to metabolize, displaying a remarkably wide diversity of metabolic trajectories from which adaptation events can be anticipated. Adaptation requires the consumption of a characteristic amount of energy, indicating that it is an active process. The demonstration that metabolic trajectories predict a priori adaptation events provides the first evidence of tight energetic coupling between metabolism and regulatory reorganization in adaptation.\n\nOne Sentence SummaryDemonstration of the tight coupling between metabolic activity and regulatory processes during rapid adaptation at the single-cell level.

systems biology↗