Biology subjects

Ares, S.

Publications and source records attributed to Ares, S..

5 recordsLinked to original sources

bioRxiv2026

Exploiting outer-membrane protein promiscuity to induce transient collateral sensitivity via efflux pump competition

In the fight against antimicrobial resistance, the identification of robust collateral sensitivity (CS) patterns could form the basis of successful sequential and combinatorial antimicrobial therapies. While most of the focus has been devoted to study stable CS due to mutations, CS can be transiently induced in Pseudomonas aeruginosa using dequalinium chloride (DC), which increases the expression of the efflux operon mexCD-oprJ. This leads to transient CS to the aminoglycoside tobramycin, whose molecular mechanism remains unclear. Using a combination of experimental results, mechanistic mathematical models and structural simulations, we show that the inactivation of NfxB by DC not only increases mexCD expression but also reduces the effective amount of the MexXY-OprM aminoglycosides efflux pump. Our data suggest that, under conditions of high MexCD production, this efflux pump can outcompete MexXY for the outer-membrane protein OprM, thereby inducing CS to tobramycin. Bayesian fits accurately reproduce measured mexCD expression and minimal inhibitory concentration (MIC) shifts across DC doses. Model predictions were validated in P. aeruginosa PA14 mutants lacking functional outer-membrane channels. Loss of OprJ preserves DC-induced CS to tobramycin, whereas loss of OprM abolishes it. These results identify competition for OprM as the proximal cause of DC-induced, transient CS and provide a generalizable framework for eliciting CS by perturbing shared components of multidrug efflux systems. This strategy suggests immediate avenues to enhance aminoglycoside efficacy while minimizing selection for stable resistance.

microbiology↗

bioRxiv2025

Spatial dynamics and emergent properties of pLS20 conjugation on solid surfaces

Horizontal gene transfer (HGT) is a major evolutionary process in bacteria, driving the dissemination of genetic traits including antibiotic resistance (AR). In this study, we employ a hybrid modeling approach, combining agent-based simulations and Ordinary Differential Equation (ODE) models, to investigate bacterial conjugation--a key HGT mechanism whose dynamics remain poorly understood. Our agent-based simulations of the transfer dynamics of the conjugative plasmid pLS20 from Bacillus subtilis reveal that spatial organization, colony growth dynamics, and quorum-sensing regulation significantly influence plasmid dissemination. Increased donor-recipient mixing enhances plasmid transmission by reducing quorum-induced repression, while colony growth-driven displacement of donor cells alters the local distribution of quorum-sensing signals, enabling sustained conjugation activity at the colony periphery. Complementary ODE modeling captures macroscopic trends in plasmid transmission, providing insights into the interplay between spatial factors and regulatory mechanisms. By bridging single-cell regulatory dynamics with population-level behaviors, this study advances our understanding of bacterial conjugation on solid surfaces, offering potential strategies for mitigating the spread of antibiotic resistance. Author summaryBacteria can exchange genetic material through a process called horizontal gene transfer, which helps them adapt to new environments but also develop traits like antibiotic resistance. One of the most important ways bacteria share genes is through conjugation--a mechanism where a conjugative element transfers from a donor to a recipient via a channel connecting both cells. Although considerable knowledge has been gathered over the last decades concerning regulation of the conjugation genes and the structure of the transferosome responsible for transfer of the conjugative element, far less is known about the dynamics of conjugative transfers within populations of cells, especially on solid medium. Our study focuses on the conjugative plasmid pLS20 from Bacillus subtilis, a model bacterium related to several pathogens. Using computer simulations, we modeled how this plasmid spreads within bacterial colonies growing on solid surfaces. We found that the spatial organization of bacteria plays a large role: well-mixed populations allow the plasmid to spread more effectively, while certain growth patterns disrupt the signaling processes that regulate gene transfer. This study helps us better understand how bacteria transfer genes in complex environments and could guide new strategies to combat antibiotic resistance.

systems biology↗

bioRxiv2023

Feedback control of organ size precision is mediated by BMP2-regulated apoptosis in the Drosophila eye

Biological processes are intrinsically noisy and yet, the result of development -like the species-specific size and shape of organs- is usually remarkably precise. This precision suggests the existence of mechanisms of feedback control that ensure that deviations from a target size are minimized. Still, we have very limited understanding of how these mechanisms operate. Here, we investigate the problem of organ size precision using the Drosophila eye. The size of the adult eye depends on the rates at which eye progenitor cells grow and differentiate. We first find that the progenitor net growth rate results from the balance between their proliferation and apoptosis, with this latter contributing to determining both final eye size and its variability. In turn, apoptosis of progenitor cells is hampered by Dpp, a BMP2/4 signaling molecule transiently produced by early differentiating retinal cells. Our genetic and computational experiments show how the status of retinal differentiation is communicated to progenitors through the differentiation-dependent production of Dpp which, by adjusting the rate of apoptosis, exerts a feedback control over the net growth of progenitors to reduce final eye size variability.

developmental biology↗

bioRxiv2021

Terminal heterocyst differentiation in the Anabaena patA mutant as a result of post-transcriptional modifications and molecular leakage

The Anabaena genus is a model organism of filamentous cyanobacteria whose vegetative cells can differentiate under nitrogen-limited conditions into a type of cell called heterocyst. These heterocysts lose the possibility to divide and are necessary for the colony because they can fix and share environmental nitrogen. In order to distribute the nitrogen efficiently, heterocysts are arranged to form a quasi-regular pattern whose features are maintained as the filament grows. Recent efforts have allowed advances in the understanding of the interactions and genetic mechanisms underlying this dynamic pattern. However, the main role of the patA and hetF genes are yet to be clarified; in particular, the patA mutant forms heterocysts almost exclusively in the terminal cells of the filament. In this work, we investigate the function of these genes and provide a theoretical model that explains how they interact within the broader genetic network, reproducing their knock-out phenotypes in several genetic backgrounds, including a nearly uniform concentration of HetR along the filament for the patA mutant. Our results suggest a role of hetF and patA in a post-transcriptional modification of HetR which is essential for its regulatory function. In addition, the existence of molecular leakage out of the filament in its boundary cells is enough to explain the preferential appearance of terminal heterocysts, without any need for a distinct regulatory pathway. Author summaryUnderstanding multicellular pattern formation is key for the study of both natural and synthetic developmental processes. Arguably one of the simplest model systems for this is the filamentous cyanobacterium Anabaena, that in conditions of nitrogen deprivation undergoes a dynamical differentiation process that differentiates roughly one in every ten cells into nitrogen-fixing heterocysts, in a quasi-regular pattern that is maintained as the filament keeps growing. One of the most characteristic mutations affecting this process forms heterocysts mostly constrained to the terminal cells of the filament. We have used experimental observations to propose a mathematical model of heterocyst differentiation able to reproduce this striking phenotype. The model extends our understanding of the regulations in this pattern-forming system and makes several predictions on molecular interactions. Importantly, a key aspect is the boundary condition at the filaments ends: inhibitors of differentiation should be able to leak out of the filament, or otherwise the terminal cells would not differentiate. This highlights, in a very clear example, the importance of considering physical constraints in developmental processes.

systems biology↗

bioRxiv2021

Day length-dependent thermal COP1 dynamics integrate conflicting seasonal cues in the control of Arabidopsis elongation

As the summer approaches, plants experience enhanced light inputs and elevated temperatures, two environmental cues with an opposite morphogenic impact. How plants integrate this conflicting information throughout seasons remains unclear. Key components of the plant response to light and temperature include phytochrome B (phyB), PHYTOCROME INTERACTING FACTOR 4 (PIF4), EARLY FLOWERING 3 (ELF3) and CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1). Here, we used hypocotyl lengths of single and double mutant/over-expression lines to fit a mathematical model incorporating known interactions of these genes. The fitted model recapitulates day length-dependent thermoelongation of all lines studied, and correctly predicts temperature responsiveness of new genotypes. Whilst previous works pointed to a lightindependent thermal function of COP1, simulations of our model suggested that COP1 has a role in temperature-signaling only during daytime. Based on by this prediction, we show that COP1 overexpression increases thermal response in continuous white light, while it has little effect in darkness. Defective thermal response of cop1-4 mutants is epistatic to phyB-9 and elf3-8, indicating that COP1 activity is essential to the transduction of phyB and ELF3 thermosensory function. Our model accurately captures phyB, ELF3 and PIF4 dynamics, providing an excellent toolbox for identification of best allelic combinations towards optimized crops resilience to climate change at different geographical latitudes.

plant biology↗