Person: RapĂșn Araiz, Beatriz
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RapĂșn Araiz
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Beatriz
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ProducciĂłn Agraria
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0000-0002-3077-810X
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811068
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Publication Open Access Antibiofilm activity of flavonoids on staphylococcal biofilms through targeting BAP amyloids(Nature Research, 2020) Matilla Cuenca, Leticia; Gil Puig, Carmen; Cuesta Ferre, Sergio; RapĂșn Araiz, Beatriz; Mira, Alex; Lasa Uzcudun, Ăñigo; Valle Turrillas, Jaione; ZiemitĂ©, MiglĂ©; Ciencias de la Salud; Osasun Zientziak; Gobierno de Navarra / Nafarroako Gobernua, PI011 KILL-BACTThe opportunistic pathogen Staphylococcus aureus is responsible for causing infections related to indwelling medical devices, where this pathogen is able to attach and form biofilms. The intrinsic properties given by the self-produced extracellular biofilm matrix confer high resistance to antibiotics, triggering infections difficult to treat. Therefore, novel antibiofilm strategies targeting matrix components are urgently needed. The biofilm associated protein, Bap, expressed by staphylococcal species adopts functional amyloid-like structures as scaffolds of the biofilm matrix. In this work we have focused on identifying agents targeting Bap-related amyloid-like aggregates as a strategy to combat S. aureus biofilm-related infections. We identified that the flavonoids, quercetin, myricetin and scutellarein specifically inhibited Bap-mediated biofilm formation of S. aureus and other staphylococcal species. By using in vitro aggregation assays and the cell-based methodology for generation of amyloid aggregates based on the Curli-Dependent Amyloid Generator system (C-DAG), we demonstrated that these polyphenols prevented the assembly of Bap-related amyloid-like structures. Finally, using an in vivo catheter infection model, we showed that quercetin and myricetin significantly reduced catheter colonization by S. aureus. These results support the use of polyphenols as anti-amyloids molecules that can be used to treat biofilm-related infections.Publication Open Access Imipenem heteroresistance but not tolerance in Haemophilus influenzae during chronic lung infection associated with chronic obstructive pulmonary disease(Frontiers Media, 2023) Gil Campillo, Celia; GonzĂĄlez-DĂaz, Aida; RapĂșn Araiz, Beatriz; Iriarte-Elizaintzin, Oihane; Elizalde GutiĂ©rrez, Iris; FernĂĄndez Calvet, Ariadna; LĂĄzaro-DĂez, MarĂa; MartĂ, Sara; Garmendia GarcĂa, Juncal; Ciencias; Zientziak; Institute for Multidisciplinary Research in Applied Biology - IMABAntibiotic resistance is a major Public Health challenge worldwide. Mechanisms other than resistance are described as contributors to therapeutic failure. These include heteroresistance and tolerance, which escape the standardized procedures used for antibiotic treatment decision-making as they do not involve changes in minimal inhibitory concentration (MIC). Haemophilus influenzae causes chronic respiratory infection and is associated with exacerbations suffered by chronic obstructive pulmonary disease (COPD) patients. Although resistance to imipenem is rare in this bacterial species, heteroresistance has been reported, and antibiotic tolerance cannot be excluded. Moreover, development of antibiotic heteroresistance or tolerance during within-host H. influenzae pathoadaptive evolution is currently unknown. In this study, we assessed imipenem resistance, heteroresistance and tolerance in a previously sequenced longitudinal collection of H. influenzae COPD respiratory isolates. The use of Etest, disc diffusion, population analysis profiling, tolerance disc (TD)-test methods, and susceptibility breakpoint criteria when available, showed a significant proportion of imipenem heteroresistance with differences in terms of degree among strains, absence of imipenem tolerance, and no specific trends among serial and clonally related strains could be established. Analysis of allelic variation in the ftsI, acrA, acrB, and acrR genes rendered a panel of polymorphisms only found in heteroresistant strains, but gene expression and genome-wide analyses did not show clear genetic traits linked to heteroresistance. In summary, a significant proportion of imipenem heteroresistance was observed among H. influenzae strains isolated from COPD respiratory samples over time. These data should be useful for making more accurate clinical recommendations to COPD patients.Publication Open Access Systematic reconstruction of the complete two-component sensorial network in staphylococcus aureus(American Society for Microbiology, 2020) RapĂșn Araiz, Beatriz; Haag, Andreas F.; Gil Puig, Carmen; Dorado Morales, Pedro; Lasa Uzcudun, Ăñigo; Ciencias de la Salud; Osasun ZientziakIn bacteria, adaptation to changes in the environment is mainly controlled through two-component signal transduction systems (TCSs). Most bacteria contain dozens of TCSs, each of them responsible for sensing a different range of signals and controlling the expression of a repertoire of target genes (regulon). Over the years, identification of the regulon controlled by each individual TCS in different bacteria has been a recurrent question. However, limitations associated with the classical approaches used have left our knowledge far from complete. In this report, using a pioneering approach in which a strain devoid of the complete nonessential TCS network was systematically complemented with the constitutively active form of each response regulator, we have reconstituted the regulon of each TCS of S. aureus in the absence of interference between members of the family. Transcriptome sequencing (RNA-Seq) and proteomics allowed us to determine the size, complexity, and insulation of each regulon and to identify the genes regulated exclusively by one or many TCSs. This gain-of-function strategy provides the first description of the complete TCS regulon in a living cell, which we expect will be useful to understand the pathobiology of this important pathogen. IMPORTANCE Bacteria are able to sense environmental conditions and respond accordingly. Their sensorial system relies on pairs of sensory and regulatory proteins, known as two-component systems (TCSs). The majority of bacteria contain dozens of TCSs, each of them responsible for sensing and responding to a different range of signals. Traditionally, the function of each TCS has been determined by analyzing the changes in gene expression caused by the absence of individual TCSs. Here, we used a bacterial strain deprived of the complete TC sensorial system to introduce, one by one, the active form of every TCS. This gain-of-function strategy allowed us to identify the changes in gene expression conferred by each TCS without interference of other members of the family.Publication Open Access Inhibiting the twoâcomponent system GraXRS with verteporfin to combat Staphylococcus aureus infections(Nature Research, 2020) Prieto Mariscal, Juana MarĂa; RapĂșn Araiz, Beatriz; Gil Puig, Carmen; PenadĂ©s, JosĂ© R.; Lasa Uzcudun, Ăñigo; Latasa Osta, Cristina; Ciencias de la Salud; Osasun ZientziakInfections caused by Staphylococcus aureus pose a serious and sometimes fatal health issue. With the aim of exploring a novel therapeutic approach, we chose GraXRS, a Two-Component System (TCS) that determines bacterial resilience against host innate immune barriers, as an alternative target to disarm S. aureus. Following a drug repurposing methodology, and taking advantage of a singular staphylococcal strain that lacks the whole TCS machinery but the target one, we screened 1.280 offpatent FDA-approved drug for GraXRS inhibition. Reinforcing the connection between this signaling pathway and redox sensing, we found that antioxidant and redox-active molecules were capable of reducing the expression of the GraXRS regulon. Among all the compounds, verteporfin (VER) was really efficient in enhancing PMN-mediated bacterial killing, while topical administration of such drug in a murine model of surgical wound infection significantly reduced the bacterial load. Experiments relying on the chemical mimicry existing between VER and heme group suggest that redox active residue C227 of GraS participates in the inhibition exerted by this FDA-approved drug. Based on these results, we propose VER as a promising candidate for sensitizing S. aureus that could be helpful to combat persistent or antibiotic-resistant infections.Publication Open Access In vitro modeling of polyclonal infection dynamics within the human airways by Haemophilus influenzae differential fluorescent labeling(American Society for Microbiology, 2023) RapĂșn Araiz, Beatriz; Sorzabal-Bellido, Ioritz; Asensio LĂłpez, Javier; LĂĄzaro-DĂez, MarĂa; Ariz Galilea, Mikel; Sobejano de la Merced, Carlos; Euba, Begoña; FernĂĄndez Calvet, Ariadna; CortĂ©s DomĂnguez, IvĂĄn; Burgui Erice, Saioa; Toledo Arana, Alejandro; Ortiz de SolĂłrzano, Carlos; Garmendia GarcĂa, Juncal; IngenierĂa ElĂ©ctrica, ElectrĂłnica y de ComunicaciĂłn; Ingeniaritza Elektrikoa, Elektronikoa eta Telekomunikazio Ingeniaritza; Institute of Smart Cities - ISCStandardized clinical procedures for antibiotic administration rely on pathogen identification and antibiotic susceptibility testing, often performed on single-colony bacterial isolates. For respiratory pathogens, this could be questionable, as chronic patients may be persistently colonized by multiple clones or lineages from the same bacterial pathogen species. Indeed, multiple strains of nontypeable Haemophilus influenzae, with different antibiotic susceptibility profiles, can be co-isolated from cystic fibrosis and chronic obstructive pulmonary disease sputum specimens. Despite this clinical evidence, we lack information about the dynamics of H. influenzae polyclonal infections, which limits the optimization of therapeutics. Here, we present the engineering and validation of a plasmid toolkit (pTBH, toolbox for Haemophilus), with standardized modules consisting of six reporter genes for fluorescent or bioluminescent labeling of H. influenzae. This plasmid set was independently introduced in a panel of genomically and phenotypically different H. influenzae strains, and two of them were used as a proof of principle to analyze mixed biofilm growth architecture and antibiotic efficacy, and to visualize the dynamics of alveolar epithelial co-infection. The mixed biofilms showed a bilayer architecture, and antibiotic efficacy correlated with the antibiotic susceptibility of the respective single-species strains. Furthermore, differential kinetics of bacterial intracellular location within subcellular acidic compartments were quantified upon co-infection of cultured airway epithelial cells. Overall, we present a panel of novel plasmid tools and quantitative image analysis methods with the potential to be used in a whole range of bacterial host species, assay types, andÂżor conditions and generate meaningful information for clinically relevant settings.Publication Open Access The impact of two-component sensorial network in staphylococcal speciation(Elsevier, 2020) RapĂșn Araiz, Beatriz; Haag, Andreas F.; Solano Goñi, Cristina; Lasa Uzcudun, Ăñigo; Ciencias de la Salud; Osasun ZientziakBacteria use two-component systems (TCSs) to sense and respond to their environments. Free-living bacteria usually contain dozens of TCSs, each of them responsible for sensing and responding to a different range of signals. Differences in the content of two-component systems are related with the capacity of the bacteria to colonize different niches or improve the efficiency to grow under the conditions of the existing niche. This review highlights differences in the TCS content between Staphylococcus aureus and Staphylococcus saprophyticus as a case study to exemplify how the ability to sense and respond to the environment is relevant for bacterial capacity to colonize and survive in/on different body surfaces.Publication Open Access CaracterizaciĂłn del sistema sensorial de dos componentes de Staphylococcus aureus(2020) RapĂșn Araiz, Beatriz; Lasa Uzcudun, Ăñigo; Ciencias de la Salud; Osasun ZientziakEn este trabajo de tesis hemos evaluado dos aproximaciones diferentes dedicadas a la bĂșsqueda de fĂĄrmacos que tengan como diana de acciĂłn los TCSs. Por un lado, dentro del proyecto 'Nuevas estrategias para el control de infecciones nosocomiales (RTC-2015-3184-1) hemos participado en la evaluaciĂłn de una colecciĂłn de fĂĄrmacos aprobados por la FDA (colecciĂłn Prestwick) para distintas patologĂas como posibles agentes antimicrobianos frente a S. aureus. El objetivo era reconvertir alguno de estos fĂĄrmacos (repurposing) y que ademĂĄs de utilizarse para la finalidad para la que fue descrito, tambiĂ©n actuara como antimicrobiano. En el caso concreto de nuestro estudio, el escrutinio se hizo frente al TCS GraRS. La segunda estrategia, recogida en el cuarto capĂtulo de esta tesis, ha consistido en el desarrollo de dos terapias alternativas frente a S. aureus basadas en inmunoterapias: anticuerpos monoclonales y nanoanticuerpos. Para ello, hemos elegido como diana de acciĂłn la HK del TCS esencial WalKR, en particular los anticuerpos se han generado frente al dominio de uniĂłn a ligando (ligand-bindig domain, LBD) de la HK. La elecciĂłn de esta diana se debe a dos razones, por un lado, se trata del Ășnico TCS esencial de S. aureus y, por otro lado, ensayos realizados con sueros de pacientes infectados por S. aureus mostraron la presencia de anticuerpos frente a este dominio. A lo largo de la tesis hemos producido anticuerpos monoclonales y nanoanticuerpos frente a diferentes epĂtopos del LBD. Hemos realizado diferentes ensayos para probar el reconocimiento de la proteĂna tanto in vitro como in vivo y para analizar el efecto de los anticuerpos en el crecimiento de S. aureus. Los ensayos preliminares indican que varios de los nanoanticuerpos desarrollados activan el crecimiento de la bacteria en lugar de reducir su crecimiento. Este resultado, aunque inesperado, indica que es posible desarrollar nanoanticuerpos capaces de afectar la funcionalidad de la HK y por tanto de bloquear su actividad.Publication Open Access Sensory deprivation in Staphylococcus aureus(Springer Nature, 2018) Villanueva San MartĂn, Maite; GarcĂa MartĂnez, Begoña; Valle Turrillas, Jaione; RapĂșn Araiz, Beatriz; Ruiz de los Mozos Aliaga, Igor; Solano Goñi, Cristina; MartĂ, Miguel; PenadĂ©s, JosĂ© R.; Toledo Arana, Alejandro; Lasa Uzcudun, Ăñigo; IdAB. Instituto de AgrobiotecnologĂa / Agrobioteknologiako InstitutuaBacteria use two-component systems (TCSs) to sense and respond to environmental changes. The core genome of the major human pathogen Staphylococcus aureus encodes 16 TCSs, one of which (WalRK) is essential. Here we show that S. aureus can be deprived of its complete sensorial TCS network and still survive under growth arrest conditions similarly to wild-type bacteria. Under replicating conditions, however, the WalRK system is necessary and sufficient to maintain bacterial growth, indicating that sensing through TCSs is mostly dispensable for living under constant environmental conditions. Characterization of S. aureus derivatives containing individual TCSs reveals that each TCS appears to be autonomous and self-sufficient to sense and respond to specific environmental cues, although some level of cross-regulation between non-cognate sensor-response regulator pairs occurs in vivo. This organization, if confirmed in other bacterial species, may provide a general evolutionarily mechanism for flexible bacterial adaptation to life in new niches.