(FBIOyF) Departamento de Química Orgánica - Artículos
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Ítem Acceso Abierto A coiled coil switch mediates cold sensing by the thermosensory protein DesK(Wiley, 2015-10-08) Saita, Emilio Adolfo; Abriata, Luciano Andrés; Tsai, Yi-Ting; Trajtenberg, Felipe; Lemmin, Thomas; Buschiazzo, Alejandro; Dal Peraro, Matteo; De Mendoza, Diego; Albanesi, DanielaThe thermosensor histidine kinase DesK from Bacillus subtilis senses changes in membrane fluidity initiating an adaptive response. Structural changes in DesK have been implicated in transmembrane signaling, but direct evidence is still lacking. On the basis of structure-guided mutagenesis, we now propose a mechanism of DesK-mediated signal sensing and transduction. The data indicate that stabilization/destabilization of a 2-helix coiled coil, which connects the transmembrane sensory domain of DesK to its cytosolic catalytic region, is crucial to control its signaling state. Computational modeling and simulations reveal couplings between protein, water and membrane mechanics. We propose that membrane thickening is the main driving force for signal sensing and that it acts by inducing helix stretching and rotation prompting an asymmetric kinase-competent state. Overall, the known structural changes of the sensor kinase, as well as further dynamic rearrangements that we now predict, consistently link structure determinants to activity modulation.Ítem Acceso Abierto The pleiotropic transcriptional regulator NlpR contributes to the modulation of nitrogen metabolism, lipogenesis and triacylglycerol accumulation in oleaginous rhodococci(Wiley, 2016-11-25) Hernández, Martín Alejandro; Lara, María Julia; Gago, Gabriela; Gramajo, Hugo Cesar; Álvarez, Héctor ManuelThe regulatory mechanisms involved in lipogenesis and triacylglycerol (TAG) accumulation are largely unknown in oleaginous rhodococci. In this study a regulatory protein (here called NlpR: Nitrogen lipid Regulator), which contributes to the modulation of nitrogen metabolism, lipogenesis and triacylglycerol accumulation in oleaginous rhodococci was identified. Under nitrogen deprivation conditions, in which TAG accumulation is stimulated, the nlpR gene was significantly upregulated, whereas a significant decrease of its expression and TAG accumulation occurred when cerulenin was added. The nlpR disruption negatively affected the nitrate/nitrite reduction as well as lipid biosynthesis under nitrogen-limiting conditions. In contrast, its overexpression increased TAG production during cultivation of cells in nitrogen-rich media. A putative ‘NlpR-binding motif’ upstream of several genes related to nitrogen and lipid metabolisms was found. The nlpR disruption in RHA1 strain led to a reduced transcription of genes involved in nitrate/nitrite assimilation, as well as in fatty acid and TAG biosynthesis. Purified NlpR was able to bind to narK, nirD, fasI, plsC and atf3 promoter regions. It was suggested that NlpR acts as a pleiotropic transcriptional regulator by activating of nitrate/nitrite assimilation genes and others genes involved in fatty acid and TAG biosynthesis, in response to nitrogen deprivation.Ítem Acceso Abierto Furo[3,2-c]coumarins carrying carbon substituents at C-2 and/or C-3. Isolation, biological activity, synthesis and reaction mechanisms(Royal Society of Chemistry, 2020) Cortés, Iván; Cala, Javier L.; Bracca, Andrea Beatriz Juana; Kaufman, Teodoro Saúl; http://orcid.org/0000-0002-8069-2793; http://orcid.org/0000-0003-2647-475X; http://orcid.org/0000-0003-3173-2178The isolation, biological activity and synthesis of natural furo[3,2-c]coumarins are presented, covering mainly the developments in the last 35 years. The most relevant approaches toward the synthesis of 2- substituted, 3-substituted and 2,3-disubstituted heterocycles are also discussed, with emphasis on the efficiency of the processes and their mechanisms.Ítem Acceso Abierto Crystal structure of cis-1-phenyl-8-(pyridin-2-yl-methyl)dibenzo[1,2-c:2,1-h]-2,14-dioxa-8-aza-1-borabicyclo[4.4.0]deca-3,8-diene(International Union of Crystallography, 2017-12-01) Ledesma, Gabriela N.; Signorella, Sandra R.; Back, Davi; Schulz Lang, ErnestoThe title compound, C26H23BN2O2, was obtained as by product during synthetic attempts of a complexation reaction between the tripodal ligand H2L [N,N-bis(2-hydroxybenzyl)(pyridin-2-yl)methylamine] and manganese(III) acetate in the presence of NaBPh4. The isolated B-phenyl dioxazaborocine contains an N→B dative bond with a cis conformation. In the crystal, C—H⋯O hydrogen bonds define chains parallel to the b-axis direction. A comparative analysis with other structurally related derivatives is also included, together with a rationalization of the unexpected production of this zwitterionic heterocycle.Ítem Acceso Abierto Antifungal activity and toxicity studies of flavanones isolated from Tessaria dodoneifolia aerial parts(Elsevier, 2020) Soberón, José R.; Sgariglia, Melina A.; Carabajal Torrez, José A.; Aguilar, Franco A.; Pero, Edgardo J.I.; Sampietro, Diego A.; Fernández de Luco, Julia; Labadie, Guillermo RobertoTessaria dodoneifolia [Asteraceae] is traditionally employed in Northwestern Argentina for fungal infections treatment. We report the antifungal activity guided isolation and identification of substances from aerial parts of this species, both individually and in combination with fluconazole (FLU), against Candida albicans strains. Two antifungal flavanones were identified as naringenin (NAR) and pinocembrin (PIN). These compounds could individually inhibit the growth of C. albicans strains. Combinations of NAR and PIN with FLU were synergistic against the FLU resistant and sensitive C. albicans strains. Genotoxic and cytotoxic evaluations were also performed. NAR, PIN and their combinations with FLU did not have a genotoxic effect on Bacillus subtilis rec strains. Finally, these compounds did not show cytotoxicity at concentrations below 80 μg/mL.Ítem Acceso Abierto Mycobacterium tuberculosis FasR senses long fatty acyl-CoA through a tunnel and a hydrophobic transmission spine(Springer Nature, 2020-07-24) Lara, María Julia; Diacovich, Lautaro; Trajtenberg, Felipe; Larrieux, Nicole; Malchiodi, Emilio L.; Fernández, Marisa M.; Gago, Gabriela; Gramajo, Hugo Cesar; Buschiazzo, Alejandro; https://orcid.org/0000-0002-3339-0100; https://orcid.org/0000-0003-0427-5549; https://orcid.org/0000-0001-7501-3330; https://orcid.org/0000-0001-7668-0119; https://orcid.org/0000-0002-2509-6526Mycobacterium tuberculosis is a pathogen with a unique cell envelope including very long fatty acids, implicated in bacterial resistance and host immune modulation. FasR is a TetR-like transcriptional activator that plays a central role in sensing mycobacterial long-chain fatty acids and regulating lipid biosynthesis. Here we disclose crystal structures of M. tuberculosis FasR in complex with acyl effector ligands and with DNA, uncovering its molecular sensory and switching mechanisms. A long tunnel traverses the entire effector-binding domain, enabling long fatty acyl effectors to bind. Only when the tunnel is entirely occupied, the protein dimer adopts a rigid configuration with its DNA-binding domains in an open state, leading to DNA dissociation. The protein-folding hydrophobic core connects the two domains, and is completed into a continuous spine when the effector binds. Such a transmission spine is conserved in a large number of TetR-like regulators, offering insight into effector-triggered allosteric functional control.Ítem Acceso Abierto XacFhaB adhesin, an important Xanthomonas citri ssp. citri virulence factor, is recognized as a pathogen-associated molecular pattern(BSPP and Wiley, 2016-11-15) Garavaglia, Betiana Soledad; Zimaro, Tamara; Abriata, Luciano Andrés; Ottado, Jorgelina; Gottig, NataliaAdhesion to host tissue is one of the key steps of the bacterial pathogenic process. Xanthomonas citri ssp. citri possesses a non-fimbrial adhesin protein, XacFhaB, required for bacterial attachment, which we have previously demonstrated to be an important virulence factor for the development of citrus canker. XacFhaB is a 4753-residue-long protein with a predicted β-helical fold structure, involved in bacterial aggregation, biofilm formation and adhesion to the host. In this work, to further characterize this protein and considering its large size, XacFhaB was dissected into three regions based on bioinformatic and structural analyses for functional studies. First, the capacity of these protein regions to aggregate bacterial cells was analysed. Two of these regions were able to form bacterial aggregates, with the most amino-terminal region being dispensable for this activity. Moreover, XacFhaB shows features resembling pathogen-associated molecular patterns (PAMPs), which are recognized by plants. As PAMPs activate plant basal immune responses, the role of the three XacFhaB regions as elicitors of these responses was investigated. All adhesin regions were able to induce basal immune responses in host and non-host plants, with a stronger activation by the carboxyl-terminal region. Furthermore, pre-infiltration of citrus leaves with XacFhaB regions impaired X. citri ssp. citri growth, confirming the induction of defence responses and restraint of citrus canker. This work reveals that adhesins from plant pathogens trigger plant defence responses, opening up new pathways for the development of protective strategies for disease control.Ítem Acceso Abierto Langmuir-Blodgett monolayers holding a wound healing active compound and its effect in cell culture. A model for the study of surface mediated drug delivery systems(Elsevier, 2021-03-14) Fernández, Luciana Andrea; Reviglio, Ana Lucía; Heredia, Daniel Alejandro; Morales, Gustavo Marcelo; Santo, Marisa Rosana; Otero, Luis Alberto; Alustiza, Fabrisio Eduardo; Liaudat, Ana Cecilia; Bosch, Pablo; Larghi, Enrique Leandro; Bracca, Andrea Beatriz Juana; Kaufman, Teodoro SaúlLangmuir and Langmuir-Blodgett films holding a synthetic bioinspired wound healing active compound were used as drug-delivery platforms. Palmitic acid Langmuir monolayers were able to incorporate 2-methyltriclisine, a synthetic Triclisine derivative that showed wound healing activity. The layers proved to be stable and the nanocomposites were transferred to solid substrates. Normal human lung cells (Medical Research Council cell strain 5, MRC-5) were grown over the monomolecular Langmuir-Blodgett films that acted as a drug reservoir and delivery system. The proliferation and migration of the cells were clearly affected by the presence of 2 methyltriclisine in the amphiphilic layers. The methodology is proposed as a simple and reliable model for the study of the effects of bioactive compounds over cellular cultures.Ítem Acceso Abierto The type III protein secretion system contributes to Xanthomonas citri subsp. citri biofilm formation(Springer Nature, 2014-04-18) Zimaro, Tamara; Sgro, Germán Gustavo; Garofalo, Cecilia Graciela; Ficarra, Florencia Andrea; Ottado, Jorgelina; Gottig, Natalia; Thomas, Ludivine; Marondedze, Claudius; Gehring, ChrisBackground: Several bacterial plant pathogens colonize their hosts through the secretion of effector proteins by a Type III protein secretion system (T3SS). The role of T3SS in bacterial pathogenesis is well established but whether this system is involved in multicellular processes, such as bacterial biofilm formation has not been elucidated. Here, the phytopathogen Xanthomonas citri subsp. citri (X. citri) was used as a model to gain further insights about the role of the T3SS in biofilm formation. Results: The capacity of biofilm formation of different X. citri T3SS mutants was compared to the wild type strain and it was observed that this secretion system was necessary for this process. Moreover, the T3SS mutants adhered proficiently to leaf surfaces but were impaired in leaf-associated growth. A proteomic study of biofilm cells showed that the lack of the T3SS causes changes in the expression of proteins involved in metabolic processes, energy generation, exopolysaccharide (EPS) production and bacterial motility as well as outer membrane proteins. Furthermore, EPS production and bacterial motility were also altered in the T3SS mutants. Conclusions: Our results indicate a novel role for T3SS in X. citri in the modulation of biofilm formation. Since this process increases X. citri virulence, this study reveals new functions of T3SS in pathogenesis.Ítem Acceso Abierto Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents(MDPI, 2024-03-23) Moreno, Leydi M.; Quiroga, Jairo; Abonia, Rodrigo; Crespo Ortíz, María del Pilar; Aranaga, Carlos Andrés; Martínez-Martínez, Luis; Sortino, Maximiliano Andrés; Barreto, Mauricio; Burbano, María E.; Insuasty, Braulio; https://orcid.org/0000-0002-9451-3063; https://orcid.org/0000-0003-3256-0961; https://orcid.org/0000-0003-2160-5167; https://orcid.org/0000-0003-1806-657X; https://orcid.org/0000-0002-6091-4045; https://orcid.org/0000-0002-4271-1690; https://orcid.org/0000-0001-5361-4901; https://orcid.org/0000-0001-8371-3310This study presents the synthesis of four series of novel hybrid chalcones (20,21)a–g and (23,24)a–g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28–33)a–g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d–g, 24a–g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e–g, 33a,b,e–g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI50 values between 0.01 and 100 μM and LC50 values in the range of 4.09 μM to >100 μM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25–62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 μg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.Ítem Acceso Abierto Endocannabinoid 2-arachidonoyl glycerol increases the transcription of daf-7 in ASI neurons(Caltech Library, 2018-10-19) Galles, Celina; Prez, Gastón M.; De Mendoza, DiegoThis article investigates the effect of the endocannabinoid 2-arachidonoyl glycerol (2-AG) on the expression of the daf-7 gene in ASI neurons of nematodes. It demonstrates that daf-7 expression levels increase notably when nematodes are exposed to 2-AG. This observation is supported by fluorescence microscopy images showing elevated GFP signal in ASI neurons treated with 2-AG compared to control groups. Statistical analysis confirms a significant difference in daf-7 expression between the 2-AG treatment and solvent control conditions. The study conducted three independent experiments, analyzing a total of 70 ASI neurons for each condition. Regarding the methods, worms were cultured on solid NGM plates supplemented with bacteria and specific supplements for each experimental condition. Daf-7 expression was monitored in synchronized L1 larvae fed with Escherichia coli supplemented with either 2-AG or carrier solvent. Fluorescence microscopy was utilized to visualize GFP intensity in ASI neurons, and image analysis software quantified the data. The study concludes a robust increase in daf-7 expression in response to 2-AG treatment.Ítem Acceso Abierto An introductory classroom exercise on protein molecular model visualization and detailed analysis of protein–ligand binding(Wiley, 2013-03-23) Poeylaut-Palena, Andrés A.; Laborde, María de los ÁngelesA learning module for molecular level analysis of protein structure and ligand/drug interaction through the visualization of X-ray diffraction is presented. Using DeepView as molecular model visualization software, students learn about the general concepts of protein structure. This Biochemistry classroom exercise is designed to be carried out by following the detailed instructions that make software handling straightforward. Students learn about protein structure and gain insight into the molecular level of the interaction of two active compounds with their receptor.Ítem Acceso Abierto Expression and purification of untagged GlnK proteins from actinobacteria(EXCLI, 2017-06-27) Gerhardt, Edileusa C. M.; Moure, Vivian R.; Souza, Andrey W.; Pedrosa, Fabio O.; Souza, Emanuel M.; Diacovich, Lautaro; Gramajo, Hugo Cesar; Huergo, Luciano F.The PII protein family constitutes one of the most conserved and well distributed family of signal transduction proteins in nature. These proteins play key roles in nitrogen and carbon metabolism. PII function has been well documented in Gram-negative bacteria. However, there are very few reports describing the in vitro properties and function of PII derived from Gram-positive bacteria. Here we present the heterologous expression and efficient purification protocols for untagged PII from three Actinobacteria of medical and biotechnological interest namely: Mycobacterium tuberculosis, Rhodococcus jostii and Streptomyces coelicolor. Circular dichroism and gel filtration analysis supported that the purified proteins are correctly folded. The purification protocol described here will facilitate biochemical studies and help to uncover the biochemical functions of PII proteins in Actinobacteria.Ítem Acceso Abierto First total synthesis of chromanone A, preparation of related compounds and evaluation of their antifungal activity against Candida albicans, a biofilm forming agent(Royal Society of Chemistry, 2021-06-01) Cortés, Iván; Cordisco, Estefanía; Kaufman, Teodoro Saúl ; Sortino, Maximiliano Andrés; Svetaz, Laura Andrea; Bracca, Andrea Beatriz Juana; https://orcid.org/0000-0002-8069-2793; https://orcid.org/0000-0002-6574-1702; https://orcid.org/0000-0003-3173-2178; https://orcid.org/0000-0002-4271-1690; https://orcid.org/0000-0002-1023-1641; https://orcid.org/0000-0003-2647-475XA straightforward and convenient approach for the first total syntheses of chromanone A and a related 7-OMe substituted natural product is reported. These unique C-3 substituted 2-hydroxymethyl chromones were recently isolated as fungal metabolites. Chromanone A was synthesized in 25.3% overall yield from the readily available pyrocatechol, whereas the second natural product was prepared in 39.7% global yield. A small library of chromones, including both natural products and some of their synthetic heterocyclic precursors, was evaluated against Candida albicans ATCC 10231, a biofilm forming agent. It was found that 8-methoxy-3-methyl-4-oxo-4H-chromene-2-carbaldehyde, a partially oxidized form of chromanone A, exhibited a minimum inhibitory concentration of 7.8 μg mL−1 and significantly inhibited the yeast's virulence factors, including the adherence to buccal epithelial cells and the secretion of phospholipases, as well as the formation of germ tubes and the generation of the hyphal pseudomycelium. In addition, despite the heterocycle exhibiting non-significant inhibition of the formation of the Candida biofilm, it completely inhibited the growth of C. albicans in preformed biofilms at 62.5 μg mL−1.Ítem Acceso Abierto Engineering multilayer chemical networks(Royal Society of Chemistry, 2019) Martínez-Amezaga, Maitena; Orrillo, Gastón; Furlán, Ricardo Luis Eugenio; https://orcid.org/0000-0001-6136-0980Dynamic multilevel systems emerged in the last few years as new platforms to study thermodynamic systems. In this work, unprecedented fully communicated three-level systems are studied. First, different conditions were screened to selectively activate thiol/dithioacetal, thiol/thioester, and thiol/disulfide exchanges, individually or in pairs. Some of those conditions were applied, sequentially, to build multilayer dynamic systems wherein information, in the form of relative amounts of building blocks, can be directionally transmitted between different exchange pools. As far as we know, this is the first report of one synthetic dynamic chemical system where relationships between layers can be changed through network operationsÍtem Acceso Abierto Isolation and synthesis of cryptosanguinolentine (isocryptolepine), a naturally-occurring bioactive indoloquinoline alkaloid(Royal Society of Chemistry, 2020-05-19) Thobokholt, Elida N.; Larghi, Enrique Leandro; Bracca, Andrea Beatriz Juana ; Kaufman, Teodoro Saúl ; https://orcid.org/0000-0001-5780-6433; https://orcid.org/0000-0002-9791-4831; https://orcid.org/0000-0003-2647-475X; https://orcid.org/0000-0003-3173-2178Cryptosanguinolentine (isocryptolepine) is one of the minor naturally-occurring monomeric indoloquinoline alkaloids, isolated from the West African climbing shrub Cryptolepis sanguinolenta. The natural product displays such a simple and unique skeleton, which chemists became interested in well before it was found in Nature. Because of its structure and biological activity, the natural product has been targeted for synthesis on numerous occasions, employing a wide range of different strategies. Hence, discussed here are aspects related to the isolation of isocryptolepine, as well as the various approaches toward its total synthesis.Ítem Acceso Abierto Natural products targeting the synthesis of β(1,3)-D-glucan and chitin of the fungal cell wall. Existing drugs and recent findings(Elsevier, 2021-06-15) Curto, M. Angeles; Butassi, Estefanía; Ribas, Juan C.; Stevaz, Laura A.; Cortés, Juan C. G.Background: During the last three decades systemic fungal infections associated to immunosuppressive therapies have become a serious healthcare problem. Clinical development of new antifungals is an urgent requirement. Since fungal but not mammalian cells are encased in a carbohydrate-containing cell wall, which is required for the growth and viability of fungi, the inhibition of cell wall synthesizing machinery, such as β(1,3)-D-glucan synthases (GS) and chitin synthases (CS) that catalyze the synthesis of β(1-3)-D-glucan and chitin, respectively, represent an ideal mode of action of antifungal agents. Although the echinocandins anidulafungin, caspofungin and micafungin are clinically well-established GS inhibitors for the treatment of invasive fungal infections, much effort must still be made to identify inhibitors of other enzymes and processes involved in the synthesis of the fungal cell wall. Purpose: Since natural products (NPs) have been the source of several antifungals in clinical use and also have provided important scaffolds for the development of semisynthetic analogues, this review was devoted to investigate the advances made to date in the discovery of NPs from plants that showed capacity of inhibiting cell wall synthesis targets. The chemical characterization, specific target, discovery process, along with the stage of development are provided here. Methods: An extensive systematic search for NPs against the cell wall was performed considering all the articles published until the end of 2020 through the following scientific databases: NCBI PubMed, Scopus and Google Scholar and using the combination of the terms “natural antifungals” and “plant extracts” with “fungal cell wall”. Results: The first part of this review introduces the state of the art of the structure and biosynthesis of the fungal cell wall and considers exclusively those naturally produced GS antifungals that have given rise to both existing semisynthetic approved drugs and those derivatives currently in clinical trials. According to their chemical structure, natural GS inhibitors can be classified as 1) cyclic lipopeptides, 2) glycolipids and 3) acidic terpenoids. We also included nikkomycins and polyoxins, NPs that inhibit the CS, which have traditionally been considered good candidates for antifungal drug development but have finally been discarded after enduring unsuccessful clinical trials. Finally, the review focuses in the most recent findings about the growing field of plant-derived molecules and extracts that exhibit activity against the fungal cell wall. Thus, this search yielded sixteen articles, nine of which deal with pure compounds and seven with plant extracts or fractions with proven activity against the fungal cell wall. Regarding the mechanism of action, seven (44%) produced GS inhibition while five (31%) inhibited CS. Some of them (56%) interfered with other components of the cell wall. Most of the analyzed articles refer to tests carried out in vitro and therefore are in early stages of development.Ítem Acceso Abierto Influence of the CH/B replacement on the reactivity of boranthrene and related compounds(American Chemical Society, 2022-02-02) Cortés, Iván; Cabrera Trujillo, Jorge Juan; Fernández, IsraelThe influence of the replacement of CH groups by boron atoms on the reactivity of planar polycyclic aromatic hydrocarbons has been explored by means of computational tools. To this end, [4 + 2]-cycloaddition reactions involving anthracene and neutral boranthrene with different dienophiles such as ethylene, acetylene, and CO2 have been compared. In addition, the influence of additional fused aromatic rings (pentacene or borapentacene) on the reactivity of these species has been also explored. It was found that the B-doped systems are systematically much more reactive than their all-carbon counterparts from both kinetic and thermodynamic points of view. The observed trends in reactivity are quantitatively analyzed in detail using state-of-the-art methods, namely, the activation strain model of reactivity and the energy decomposition analysis method. Our calculations reveal the importance of molecular orbital interactions as the key factor responsible for the enhanced reactivity of the B-doped systems.Ítem Acceso Abierto Selective inhibition of the amyloid matrix of Escherichia coli biofilms by a bifunctional microbial metabolite(Nature Research, 2023-10-19) Cordisco, Estefanía; Zanor, María Inés; Moreno, Diego M.; Serra, Diego Omar; https://orcid.org/0000-0002-6574-1702; https://orcid.org/0000-0002-8903-0673; https://orcid.org/0000-0001-5493-8537; https://orcid.org/0000-0002-3926-384XThe propensity of bacteria to grow collectively in communities known as biofilms and their ability to overcome clinical treatments in this condition has become a major medical problem, emphasizing the need for anti-biofilm strategies. Antagonistic microbial interactions have extensively served as searching platforms for antibiotics, but their potential as sources for anti-biofilm compounds has barely been exploited. By screening for microorganisms that in agar-set pairwise interactions could antagonize Escherichia coli’s ability to form macrocolony biofilms, we found that the soil bacterium Bacillus subtilis strongly inhibits the synthesis of amyloid fibers –known as curli-, which are the primary extracellular matrix (ECM) components of E. coli biofilms. We identified bacillaene, a B. subtilis hybrid non-ribosomal peptide/polyketide metabolite, previously described as a bacteriostatic antibiotic, as the effector molecule. We found that bacillaene combines both antibiotic and anti-curli functions in a concentration-dependent order that potentiates the ecological competitiveness of B. subtilis, highlighting bacillaene as a metabolite naturally optimized for microbial inhibition. Our studies revealed that bacillaene inhibits curli by directly impeding the assembly of the CsgB and CsgA curli subunits into amyloid fibers. Moreover, we found that curli inhibition occurs despite E. coli attempts to reinforce its protective ECM by inducing curli genes via a RpoS-mediated competition sensing response trigged by the threatening presence of B. subtilis. Overall, our findings illustrate the relevance of exploring microbial interactions not only for finding compounds with unknown and unique activities, but for uncovering additional functions of compounds previously categorized as antibiotics.Ítem Acceso Abierto Control of brown rot produced by Monilinia fructicola in peaches ssing a full-spectrum extract of Zuccagnia punctata Cav(Multidisciplinary Digital Publishing Institute (MDPI), 2023-10-17) Di Liberto, Melina G.; Stegmayer, María Inés; Fernández, Laura; Quiroga, Ariel Darío; Svetaz, Laura Andrea; Derita, Marcos G.Brown rot of stone fruit, caused by Monilinia spp., is one of the most important diseases worldwide, causing significant production losses. Currently, the standard practices for controlling this infection consist of repetitive use of synthetic fungicides. The global tendency encourages the demand for high-quality food products harmless to health and the environment, leading to a reduction in the use of these types of substances. Zuccagnia punctata (Fabaceae) is a perennial shrub extensively used for the treatment of fungal and bacterial infections in Argentinean traditional medicine. In this study, we isolated and characterized (morphologically and molecularly) a pathogenic and virulent strain of Monilinia fructicola, which is the most hostile species of the genus. Consequently, we explored the in vitro antifungal activity of the ethanolic extract of Z. punctata against this phytopathogen. The chalcones 2´,4´-dihydroxy-3´-methoxychalcone and 2´,4´-dihydroxychalcone were isolated from the extract and evaluated against M. fructicola demonstrating that they were responsible for this activity. To promote full-spectrum extract rather than pure compounds, we performed ex-vivo assays using fresh peaches inoculated with the pathogen, and then treated by immersion in an extract solution of 250 µg/mL concentration. Treatment with Z. punctata extract did not show a statistically significant difference from commercial fungicides in the control of fruit rot. In addition, Huh7 cell cytotoxicity evaluation showed that Z. punctata extract was less cytotoxic than commercial fungicides at the assayed concentrations. Based on our research, this plant extract could potentially offer a safer alternative to commercial fungicides for treating peach brown rot.