(FBIOyF) Departamento de Bioquímica Clínica - Artículos

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2-Mercaptomethyl-thiazolidines use conserved aromatic–S interactions to achieve broad-range inhibition of metallo-β-lactamases
(Royal Society of Chemistry, 2021-01-05) Rossi, María Agustina; Martínez, Verónica; Hinchliffe, Philip; Mojica, María F.; Castillo, Valerie; Moreno, Diego M.; Smith, Ryan; Spellberg, Brad; Drusano, George L.; Banchio, Claudia; Bonomo, Robert A.; Spencer, James; Vila, Alejandro J.; Mahler, Graciela; https://orcid.org/0000-0003-4720-4070; https://orcid.org/0000-0002-3697-5219; https://orcid.org/0000-0001-8611-4743; https://orcid.org/0000-0002-1380-9824; https://orcid.org/0000-0001-5493-8537; https://orcid.org/0000-0002-4602-0571; https://orcid.org/0000-0002-7978-3233; https://orcid.org/0000-0003-0612-0516
Infections caused by multidrug resistant (MDR) bacteria are a major public health threat. Carbapenems are among the most potent antimicrobial agents that are commercially available to treat MDR bacteria. Bacterial production of carbapenem-hydrolysing metallo-β-lactamases (MBLs) challenges their safety and efficacy, with subclass B1 MBLs hydrolysing almost all β-lactam antibiotics. MBL inhibitors would fulfil an urgent clinical need by prolonging the lifetime of these life-saving drugs. Here we report the synthesis and activity of a series of 2-mercaptomethyl-thiazolidines (MMTZs), designed to replicate MBL interactions with reaction intermediates or hydrolysis products. MMTZs are potent competitive inhibitors of B1 MBLs in vitro (e.g., Ki = 0.44 μM vs. NDM-1). Crystal structures of MMTZ complexes reveal similar binding patterns to the most clinically important B1 MBLs (NDM-1, VIM-2 and IMP-1), contrasting with previously studied thiol-based MBL inhibitors, such as bisthiazolidines (BTZs) or captopril stereoisomers, which exhibit lower, more variable potencies and multiple binding modes. MMTZ binding involves thiol coordination to the Zn(II) site and extensive hydrophobic interactions, burying the inhibitor more deeply within the active site than D/L-captopril. Unexpectedly, MMTZ binding features a thioether–π interaction with a conserved active-site aromatic residue, consistent with their equipotent inhibition and similar binding to multiple MBLs. MMTZs penetrate multiple Enterobacterales, inhibit NDM-1 in situ, and restore carbapenem potency against clinical isolates expressing B1 MBLs. Based on their inhibitory profile and lack of eukaryotic cell toxicity, MMTZs represent a promising scaffold for MBL inhibitor development. These results also suggest sulphur–π interactions can be exploited for general ligand design in medicinal chemistry.
Acceso Abierto
A disordered region retains the full protease inhibitor activity and the capacity to induce CD8+ T cells in vivo of the oral vaccine adjuvant U-Omp19
(Elsevier, 2022-09-06) Darriba, María Laura; Pueblas Castro, Celeste; Coria, Lorena M.; Bruno, Laura; Cerutti, María Laura; Otero, Lisandro H.; Chemes, Lucía B.; Rasia, Rodolfo M.; Klinke, Sebastián; Cassataro, Juliana; Pasquevich, Karina A.
Acceso Abierto
A general reaction mechanism for carbapenem hydrolysis by mononuclear and binuclear metallo-β-lactamases
(Nature, 2017-09-14) Lisa, María Natalia; Palacios, Antonela R.; Aitha, Mahesh; González, Mariano M.; Moreno, Diego M.; Crowder, Michael W.; Bonomo, Robert A.; Spencer, James; Tierney, David L.; Llarrull, Leticia Irene; Vila, Alejandro J.
Acceso Abierto
A new model for Trypanosoma cruzi heme homeostasis depends on modulation of TcHTE protein expression
(American Society for Biochemistry and Molecular Biology, 2020-07-23) Pagura, Lucas; Tevere, Evelyn; Merli, Marcelo Luciano; Cricco, Julia Alejandra
Acceso Abierto
Acinetobacter baumannii response to cefiderocol challenge in human urine
(Springer Nature, 2022-05-24) Nishimura, Brent; Escalante, Jenny; Tuttobene, Marisel Romina; Subils, Tomás; Mezcord, Vyanka; Pimentel, Camila; Georgeos, Nardin; Pasteran, Fernando; Rodríguez, Cecilia; Sieira, Rodrigo; Actis, Luis A.; Tolmasky,, Marcelo E.; Bonomo, Robert A.; Ramírez, María Soledad
Cefiderocol (CFDC) is a novel chlorocatechol-substituted siderophore antibiotic approved to treat complicated urinary tract infections (cUTI) and hospital-acquired and ventilator-acquired pneumonia (HAP/VAP). Previous work determined that albumin-rich human fluids increase the minimum inhibitory concentration (MICs) of Acinetobacter baumannii against CFDC and reduce the expression of genes related to iron uptake systems. This latter effect may contribute to the need for higher concentrations of CFDC to inhibit growth. The presence of human urine (HU), which contains low albumin concentrations, did not modify MIC values of two carbapenem-resistant A. baumannii. Levels of resistance to CFDC were not modified by HU in strain AMA40 but were reduced in strain AB5075. Expanding the studies to other carbapenem-resistant A. baumannii isolates showed that the presence of HU resulted in unmodified or reduced MIC of CDFC values. The expression of piuA, pirA, bauA, and bfnH determined by qRT-PCR was enhanced in A. baumannii AMA40 and AB5075 by the presence of HU in the culture medium. All four tested genes code for functions related to recognition and transport of ferric-siderophore complexes. The effect of HU on expression of pbp1, pbp3, blaOXA-51-like, blaADC, and blaNDM-1, genes associated with resistance to β-lactams, as well as genes coding for efflux pumps and porins was variable, showing dependence with the strain analyzed. We conclude that the lack of significant concentrations of albumin and free iron in HU makes this fluid behave differently from others we tested. Unlike other albumin rich fluids, the presence of HU does not impact the antibacterial activity of CFDC when tested against A. baumannii.
Acceso Abierto
Acute diarrhoea in children: determination of duration using a combined bismuth hydroxide gel and oral rehydration solution therapy vs. oral rehydration solution
(MDPI, 2016-12-21) Oviedo, Adriana; Díaz, Mirna; Valenzuela, María Laura; Vidal, Victoria; Racca, Liliana; Bottai, Hebe; Priore, Graciela; Peluffo, Graciela; Di Bartolomeo, Susana; Cabral, Graciela; Toca, María del Carmen
Oral rehydration salt (ORS) treatment in young children with acute diarrhoea (AD) has contributed to decrease mortality associated with dehydration although effective strategies to reduce morbidity associated with this disease are required. The aim of this study was to evaluate the diarrhoea duration when using combined colloidal bismuth hydroxide gel (CBHG) and oral rehydration salt treatment compared with ORS therapy in children with AD. We designed a double-blind, randomised prospective study with treatment and control groups. Patients aged one to 12 years, with no prior pathology and with AD of less than 48 h were included. The Chi-squared and Mann-Whitney tests were used, as well as the Cox proportional hazards model and the Kaplan-Meier estimator. Patients were randomised into an ORS and CBHG treatment group and a control group for ORS plus placebo. (Average age: 3.2 years). The result of the post-treatment evaluation with respect to the average duration of AD was 25.5 h for the treated group vs. 41.5 h for the control group (p = 0.015). The average number of stools was 4.8 in the treated group and 8.2 in the control group (p = 0.032). We conclude that the use of CBHG plus ORS significantly reduced the duration of AD, the number of stools and the percentage of children with persistent AD after 24 h of treatment compared to the control group. AD remitted almost twice as fast in patients treated with CBHG and ORS compared to those who received ORS plus placebo.
Acceso Abierto
An experiment-informed signal transduction model for the role of the Staphylococcus aureus MecR1 protein in β-lactam resistance
(Springer Nature, 2019-12-20) Belluzo, Bruno Salvador; Abriata, Luciano Andrés; Giannini, Estefanía; Mihovilcevic, Damila; Dal Peraro, Matteo; Llarrull, Leticia Irene
The treatment of hospital- and community-associated infections by methicillin-resistant Staphylococcus aureus (MRSA) is a perpetual challenge. This Gram-positive bacterium is resistant specifically to β-lactam antibiotics, and generally to many other antibacterial agents. Its resistance mechanisms to β-lactam antibiotics are activated only when the bacterium encounters a β-lactam. This activation is regulated by the transmembrane sensor/signal transducer proteins BlaR1 and MecR1. Neither the transmembrane/metalloprotease domain, nor the complete MecR1 and BlaR1 proteins, are isolatable for mechanistic study. Here we propose a model for full-length MecR1 based on homology modeling, residue coevolution data, a new extensive experimental mapping of transmembrane topology, partial structures, molecular simulations, and available NMR data. Our model defines the metalloprotease domain as a hydrophilic transmembrane chamber effectively sealed by the apo-sensor domain. It proposes that the amphipathic helices inserted into the gluzincin domain constitute the route for transmission of the β-lactam-binding event in the extracellular sensor domain, to the intracellular and membrane-embedded zinc-containing active site. From here, we discuss possible routes for subsequent activation of proteolytic action. This study provides the first coherent model of the structure of MecR1, opening routes for future functional investigations on how β-lactam binding culminates in the proteolytic degradation of MecI.
Acceso Abierto
Antiphospholipid and antioangiogenic activity in females with recurrent miscarriage and antiphospholipid syndrome
(SAGE, 2016-11-02) Pelusa, Héctor Fabián; Pezzarini, Eleonora; Basiglio, Cecilia Lorena; Musuruana, Jorge; Bearzotti, Mariela; Svetaz, María José; Daniele, Stella Maris; Bottai, Hebe; Arriaga, Sandra Mónica María
Acceso Abierto
Arabidopsis thaliana Hcc1 is a Sco-like metallochaperonefor Cu A assembly in Cytochrome c Oxidase
(Wiley, 2020-12) Llases, María Eugenia; Lisa, María Natalia; Morgada, Marcos Nicolás; Giannini, Estefanía; Alzari, Pedro M.; Vila, Alejandro J.
The assembly of the CuA site in Cytochrome c Oxidase (COX) is a criticalstep for aerobic respiration in COX-dependent organisms. Several geneproducts have been associated with the assembly of this copper site, themost conserved of them belonging to the Sco family of proteins, whichhave been shown to perform different roles in different organisms. Plantsexpress two orthologs of Sco proteins: Hcc1 and Hcc2. Hcc1 is known tobe essential for plant development and for COX maturation, but its precisefunction has not been addressed until now. Here, we report the biochemi-cal, structural and functional characterization of Arabidopsis thaliana Hcc1protein (here renamed Sco1). We solved the crystal structure of the Cu+1-bound soluble domain of this protein, revealing a tri coordinated environ-ment involving a CxxxCxnH motif. We show that AtSco1 is able to workas a copper metallochaperone, inserting two Cu+1 ions into the CuA site ina model of CoxII. We also show that AtSco1 does not act as a thiol-disul-ﬁde oxido-reductase. Overall, this information sheds new light on the bio-chemistry of Sco proteins, highlighting the diversity of functions amongthem despite their high structural similarities.
Acceso Abierto
Assessing endocrine and immune parameters in human immunodeficiency virus-infected patients before and after the immune reconstitution inflammatory syndrome
(Brazilian Society of Endocrinology and Metabolism, 2018-02) Rateni, Liliana Beatriz; Lupo, Sergio; Racca, Liliana; Palazzi, Jorge; Ghersevich, Sergio Albino
Objective: The present study compares immune and endocrine parameters between HIV-infected patients who underwent the Immune Reconstitution Inflammatory Syndrome (IRIS-P) during antiretroviral therapy (ART) and HIV-patients who did not undergo the syndrome (non-IRIS-P). Materials and methods: Blood samples were obtained from 31 HIV-infected patients (15 IRIS-P and 16 non-IRIS-P) before ART (BT) and 48 ± 2 weeks after treatment initiation (AT). Plasma Interleukin-6 (IL-6) and Interleukin-18 (IL-18) were determined by ELISA. Cortisol, dehydroepiandrosterone sulfate (DHEA-S) and thyroxin concentrations were measured using chemiluminescence immune methods. Results: Concentrations of IL-6 (7.9 ± 1.9 pg/mL) and IL-18 (951.5 ± 233.0 pg/mL) were significantly higher (p < 0.05) in IRIS-P than in non-IRIS-P (3.9 ± 1.0 pg/mL and 461.0 ± 84.4 pg/mL, respectively) BT. Mean T4 plasma level significantly decreased in both groups of patients after treatment (p < 0.05). In both groups cortisol levels were similar before and after ART (p > 0.05). Levels of DHEA-S in IRIS-P decreased AT (1080.5 ± 124.2 vs. 782.5 ± 123.8 ng/mL, p < 0.05) and they were significantly lower than in non-IRIS-P (782.5 ± 123.8 vs. 1203.7 ± 144.0 ng/mL, p < 0.05). IRIS-P showed higher values of IL-6 and IL-18 BT and lower levels of DHEA-S AT than in non-IRIS-P. Conclusion: These parameters could contribute to differentiate IRIS-P from non-IRIS-P. The significant decrease in DHEA-S levels in IRIS-P after ART might suggest a different adrenal response
Acceso Abierto
Bacterially produced metabolites protect C. elegans neurons from degeneration
(Public Library of Science, 2020-03-24) Urrutia, Arles; Garcia Angulo, Victor Antonio; Fuentes, Andrés; Caneo, Mauricio; Legüe, Marcela; Urquiza Zurich, Sebastian; Delgado, Scarlett E; Ugalde, Juan; Burdisso, Paula; Calixto, Andrea
Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the mechanosensory abnormality protein 4 (MEC-4d) degenerin/epithelial Na+ (DEG/ENaC) channel, which causes the progressive degeneration of the touch receptor neurons (TRNs). Using this model, our study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. Although degeneration of TRNs was steady and completed at adulthood in the strain routinely used for C. elegans maintenance (Escherichia coli OP50), it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and was not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of DAF-16 (ortholog of the FOXO family of transcription factors), a phenomenon previously reported to underlie neuroprotection caused by down-regulation of the insulin receptor in this system. Moreover, a daf-16 loss-of-function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter γ-aminobutyric acid (GABA) and lactate as metabolites differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Additionally, lactate supplementation also increased anterior ventral microtubule (AVM) neuron survival in OP50. Together, these results demonstrate that bacterially produced GABA and other metabolites exert an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.
Acceso Abierto
Biochemistry of copper site assembly in heme-copper oxidases: a theme with variations
(MDPI, 2019-08-05) Llases, María Eugenia; Morgada, Marcos Nicolás; Vila, Alejandro J.
Acceso Abierto
Biomarkers of oxidative stress and inflammation in chagasic myocardiopathy
(Bentham Open, 2018-10) Gerrard, Gabriela; Martí, María Belén; Diviani, Romina; Ceruti, María José; Lioi, Susana; Beloscar, Juan; D'Arrigo, Mabel; Universidad Nacional de Rosario. Facultad de Ciencias Médicas. Cátedra de Cardiología: evaluación clínica de los pacientes que participaron del estudio.
Acceso Abierto
CALR, JAK2 and MPL mutation status in Argentinean patients with BCR-ABL1- negative myeloproliferative neoplasms
(Taylor & Francis, 2017-10-09) Ojeda, Mara Jorgelina; Bragós, Irma Margarita; Calvo, Karina; Williams, Gladis Marcela; Carbonell, María Magdalena; Pratti, Arianna Flavia
Acceso Abierto
Cerebrospinal fuid (CSF) augments metabolism and virulence expression factors in Acinetobacter baumannii
(Nature Research, 2021-02-26) Martínez, Jasmine; Razo Gutiérrez, Chelsea; Razo Gutiérrez, Chelsea; Courville, Robert; Pimentel, Camila; Liu, Christine; Fung, Sammie E.; Tuttobene, Marisel Romina; Phan, Kimberly; Vila, Alejandro J.; Shahrestani, Parvin; Jimenez, Veronica; Tolmasky, Marcelo E.; Becka, Scott A.; Papp Wallace, Krisztina M.; Bonomo, Robert A.; Soler Bistue, Alfonso; Sieira, Rodrigo; Ramírez, María Soledad
In a recent report by the Centers for Disease Control and Prevention (CDC), multidrug resistant (MDR) Acinetobacter baumannii is a pathogen described as an “urgent threat.” Infection with this bacterium manifests as diferent diseases such as community and nosocomial pneumonia, bloodstream infections, endocarditis, infections of the urinary tract, wound infections, burn infections, skin and soft tissue infections, and meningitis. In particular, nosocomial meningitis, an unwelcome complication of neurosurgery caused by extensivelydrug resistant (XDR) A. baumannii, is extremely challenging to manage. Therefore, understanding how A. baumannii adapts to diferent host environments, such as cerebrospinal fuid (CSF) that may trigger changes in expression of virulence factors that are associated with the successful establishment and progress of this infection is necessary. The present invitro work describes, the genetic changes that occur during A. baumannii infltration into CSF and displays A. baumannii’s expansive versatility to persist in a nutrient limited environment while enhancing several virulence factors to survive and persist. While a hypervirulent A. baumannii strain did not show changes in its transcriptome when incubated in the presence of CSF, a lowvirulence isolate showed signifcant diferences in gene expression and phenotypic traits. Exposure to 4% CSF caused increased expression of virulence factors such as fmbriae, pilins, and iron chelators, and other virulence determinants that was confrmed in various model systems. Furthermore, although CSF’s presence did not enhance bacterial growth, an increase of expression of genes encoding transcription, translation, and the ATP synthesis machinery was observed. This work also explores A. baumannii’s response to an essential component, human serum albumin (HSA), within CSF to trigger the diferential expression of genes associated with its pathoadaptibility in this environment.
Acceso Abierto
Characterisation of ST25 NDM-1-producing Acinetobacter spp. strains leading the increase in NDM-1 emergence in Argentina
(Elsevier, 2020-09-02) Rodgers, Deja; Pasteran, Fernando; Calderon, Manuel; Jaber, Sara; Traglia, German M.; Albornoz, Ezequiel; Corso, Alejandra; Vila, Alejandro J.; Bonomo, Robert A.; Adams, Mark D.; Ramírez, María Soledad
Acceso Abierto
COA6 is structurally tuned to function as a thiol-disulfide oxidoreductase in copper delivery to mitochondrial cytochrome c oxidase
(Cell Press, 2019-12-17) Soma, Shivatheja; Morgada, Marcos Nicolás; Naik, Mandar T.; Boulet, Aren; Roesler, Anna A.; Dziuba, Nathaniel; Ghosh, Alok; Yu, Qinhong; Lindahl, Paul A.; Ames, James B.; Leary, Scot C.; Vila, Alejandro J.; Gohil, Vishal M.
Acceso Abierto
Deciphering the evolution of metallo-β-lactamases: A journey from the test tube to the bacterial periplasm
(American Society for Biochemistry and Molecular Biology Inc., 2022-02-01) López, Carolina; Delmonti, Juliana; Bonomo, Robert A.; Vila, Alejandro J.
Acceso Abierto
Deficiencia de glucosa-6-fosfato deshidrogenasa eritrocitaria en Rosario
(ederación Bioquímica de la Provincia de Buenos Aires, 2012-07) Acosta, Irma del Luján; Milani, Ángela Cristina; Pérez, Susana Mabel; Lanza, Olga; Detarsio, Germán A.
Se estudió la actividad enzimática (AE) de la enzima glucosa-6-fosfato deshidrogenasa eritrocitaria (G6PD) y la movilidad electroforética (ME) en una población de hombres y mujeres de la ciudad de Rosario (provincia de Santa Fe), Argentina y zona de influencia. Para la determinación de AE se utilizó la técnica cinética de Glock y McLean y para la electroforesis de la enzima, la técnica de M.C. Rattazzi y L.C. Bernini en acetato de celulosa. Los valores normales de actividad enzimática (AE) para hombres y mujeres adultos fueron de 8,1 ± 1,4 UI G6PD/g Hb. Se demostró que los valores de AE son independientes de la edad, sexo y concentración de hemoglobina. En todos los grupos etarios estudiados no se observaron diferencias significativas de AE con respecto a los adultos normales a excepción de los neonatos que presentaron un significativo aumento de la misma, lo cual está directamente relacionado con las características fisiológicas de los eritrocitos del recién nacido. Entre los 686 individuos estudiados se detectaron 2 pacientes deficientes de G6PD, lo que dio una prevalencia de 0,3% y el patrón electroforético correspondiente a esta población fue 98% (n: 672) para G6PD B y 2% (n: 14) para G6PD con movilidad rápida tipo A.
Acceso Abierto
Differential metabolic rearrangements after cold storage are correlated with chilling injury resistance of peach fruits
(Frontiers Media, 2016-09-30) Bustamante, Claudia Anabel; Monti, Laura Lucía; Gabilondo, Julieta; Scossa, Federico; Budde, Claudio O.; Lara, María Valeria; Fernie, Alisdair R.; Drincovich, María Fabiana

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