Enterococcus faecalis inhibits Klebsiella pneumoniae growth in polymicrobial biofilms in a glucose-enriched medium

Catheter-related urinary tract infections are one of the most common biofilm-associated diseases. Within biofilms, bacteria cooperate, compete, or have neutral interactions. This study aimed to investigate the interactions in polymicrobial biofilms of Klebsiella pneumoniae and Enterococcus faecalis, two of the most common uropathogens. Although K. pneumoniae was the most adherent strain, it could not maintain dominance in the polymicrobial biofilm due to the lactic acid produced by E. faecalis in a glucose-enriched medium. This result was supported by the use of E. faecalis V583 ldh-1/ldh-2 double mutant (non-producer of lactic acid), which did not inhibit the growth of K. pneumoniae. Lyophilized cell-free supernatants obtained from E. faecalis biofilms also showed antimicrobial/anti-biofilm activity against K. pneumoniae. Conversely, there were no significant differences in planktonic polymicrobial cultures. In summary, E. faecalis modifies the pH by lactic acid production in polymicrobial biofilms, which impairs the growth of K. pneumoniae

A C˄S-cyclometallated gold(III) complex as novel antibacterial candidate against drug-resistant bacteria

The worldwide emergence and spread of infections caused by multidrug-resistant bacteria endangers the efficacy of current antibiotics in the clinical setting. The lack of new antibiotics in the pipeline points to the need of developing new strategies. Recently, gold-based drugs are being repurposed for antibacterial applications. Among them, gold(III) complexes have received increasing attention as metal-based anticancer agents. However, reports on their antibacterial activity are scarce due to stability issues. The present work demonstrates the antibacterial activity of the gold(III) complex 2 stabilized as C∧S-cycloaurated containing a diphenylphosphinothioic amide moiety, showing minimum inhibitory concentration (MIC) values that ranged from 4 to 8 and from 16 to 32 mg/L among Gram-positive and Gram-negative multidrug-resistant (MDR) pathogens, respectively. Complex 2 has a biofilm inhibitory activity of only two to four times than its MIC. We also describe for the first time a potent antibacterial synergistic effect of a gold(III) complex combined with colistin, showing a bactericidal effect in less than 2 h; confirming the role of the outer membrane as a permeability barrier. Complex 2 shows a low rate of internalization in Staphylococcus aureus and Acinetobacter baumannii; it does not interact with replication enzymes or efflux pumps, causes ultrastructural damages in both membrane and cytoplasmic levels, and permeabilizes the bacterial membrane. Unlike control antibiotics, complex 2 did not generate resistant mutants in 30-day sequential cultures. We detected lower cytotoxicity in a non-tumoral THLE-2 cell line (IC50 = 25.5 μM) and no acute toxicity signs in vivo after an i.v. 1-mg/kg dose. The characterization presented here reassures the potential of complex 2 as a new chemical class of antimicrobial agents

Gold(III) Complexes Activity Against Multidrug-Resistant Bacteria Of Veterinary Significance

The emergence and spread of multidrug-resistant bacteria are a global concern. The lack of new antibiotics in the pipeline points to the need for developing new strategies. In this sense, gold(III) complexes (G3Cs) could be a promising alternative due to their recently described antibacterial activity. The aim of this study was to evaluate the antimicrobial activity of G3Cs alone and in combination with colistin against pathogenic bacteria from veterinary sources. Minimal inhibitory concentration (MIC) values were determined by broth microdilution and compared with clinically relevant antibiotics. Antibiofilm activity was determined by crystal violet staining. Combinations of selected G3Cs with colistin and cytotoxicity in commercial human cell lines were evaluated. Four and seven G3Cs showed antibacterial effect against Gram-negative and Gram-positive strains, respectively, with this activity being higher among Gram-positive strains. The G3Cs showed antibiofilm activity against Gram-negative species at concentrations similar or one to four folds higher than the corresponding MICs. Combination of G3Cs with colistin showed a potential synergistic antibacterial effect reducing concentrations and toxicity of both agents. The antimicrobial and antibiofilm activity, the synergistic effect when combined with colistin and the in vitro toxicity suggest that G3Cs would provide a new therapeutic alternative against multidrug-resistant bacteria from veterinary origin

Real-Time Selective Harmonic Mitigation Technique for Power Converters Based on the Exchange Market Algorithm

Hand-in-hand with the smart-grid paradigm development, power converters used in high-power applications are facing important challenges related to efficiency and power quality. To overcome these issues, the pre-programmed Pulse-Width Modulation (PWM) methods have been extensively applied to reduce the harmonic distortion with very low power switching losses for high-power converters. Among the pre-programmed PWM techniques, Selective Harmonic Elimination (SHE) has been the prevailing solution, but recently, Selective Harmonic Mitigation (SHM) stands as a superior alternative to provide further control of the harmonic spectrum with similar losses. However, the large computational burden required by the SHM method to find a solution confines it as an off-line application, where the switching set valid solutions are pre-computed and stored in a memory. In this paper, for the first time, a real-time implementation of SHM using an off-the-shelf mid-range microcontroller is presented and tested. The Exchange Market Algorithm (EMA), initially focused on optimizing financial transactions, is considered and executed to achieve the SHM targets. The performance of the EMA-based SHM is presented showing experimental results considering a reduced number of switching angles applied to a specific three-level converter, but the method can be extrapolated to any other three-level converter topology.Ministerio de Ciencia e Innovación de España TEC2016-78430-RJunta de Andalucía P18-RT-1340Fondo Nacional de Investigación de Qatar NPRP 9-310-2-13

In vitro and in vivo Virulence Potential of the Emergent Species of the Acinetobacter baumannii (Ab) Group

The increased use of molecular identification methods and mass spectrometry has revealed that Acinetobacter spp. of the A. baumannii (Ab) group other than A. baumannii are increasingly being recovered from human samples and may pose a health challenge if neglected. In this study 76 isolates of 5 species within the Ab group (A. baumannii n = 16, A. lactucae n = 12, A. nosocomialis n = 16, A. pittii n = 20, and A. seifertii n = 12), were compared in terms of antimicrobial susceptibility, carriage of intrinsic resistance genes, biofilm formation, and the ability to kill Caenorhabditis elegans in an infection assay. In agreement with previous studies, antimicrobial resistance was common among A. baumannii while all other species were generally more susceptible. Carriage of genes encoding different efflux pumps was frequent in all species and the presence of intrinsic class D β-lactamases was reported in A. baumannii, A. lactucae (heterotypic synonym of A. dijkshoorniae) and A. pittii but not in A. nosocomialis and A. seifertii. A. baumannii and A. nosocomialis presented weaker pathogenicity in our in vitro and in vivo models than A. seifertii, A. pittii and, especially, A. lactucae. Isolates from the former species showed decreased biofilm formation and required a longer time to kill C. elegans nematodes. These results suggest relevant differences in terms of antibiotic susceptibility patterns among the members of the Ab group as well as highlight a higher pathogenicity potential for the emerging species of the group in this particular model. Nevertheless, the impact of such potential in the human host still remains to be determined

E14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response

e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript

Novel gold(III)-dithiocarbamate complex targeting bacterial thioredoxin reductase: antimicrobial activity, synergy, toxicity, and mechanistic insights

IntroductionAntimicrobial resistance is a pressing global concern that has led to the search for new antibacterial agents with novel targets or non-traditional approaches. Recently, organogold compounds have emerged as a promising class of antibacterial agents. In this study, we present and characterize a (C^S)-cyclometallated Au(III) dithiocarbamate complex as a potential drug candidate.Methods and resultsThe Au(III) complex was found to be stable in the presence of effective biological reductants, and showed potent antibacterial and antibiofilm activity against a wide range of multidrug-resistant strains, particularly gram-positive strains, and gram-negative strains when used in combination with a permeabilizing antibiotic. No resistant mutants were detected after exposing bacterial cultures to strong selective pressure, indicating that the complex may have a low propensity for resistance development. Mechanistic studies indicate that the Au(III) complex exerts its antibacterial activity through a multimodal mechanism of action. Ultrastructural membrane damage and rapid bacterial uptake suggest direct interactions with the bacterial membrane, while transcriptomic analysis identified altered pathways related to energy metabolism and membrane stability including enzymes of the TCA cycle and fatty acid biosynthesis. Enzymatic studies further revealed a strong reversible inhibition of the bacterial thioredoxin reductase. Importantly, the Au(III) complex demonstrated low cytotoxicity at therapeutic concentrations in mammalian cell lines, and showed no acute in vivo toxicity in mice at the doses tested, with no signs of organ toxicity.DiscussionOverall, these findings highlight the potential of the Au(III)-dithiocarbamate scaffold as a basis for developing novel antimicrobial agents, given its potent antibacterial activity, synergy, redox stability, inability to produce resistant mutants, low toxicity to mammalian cells both in vitro and in vivo, and non-conventional mechanism of action

Clinical Escherichia coli: From Biofilm Formation to New Antibiofilm Strategies

Escherichia coli is one of the species most frequently involved in biofilm-related diseases, being especially important in urinary tract infections, causing relapses or chronic infections. Compared to their planktonic analogues, biofilms confer to the bacteria the capacity to be up to 1000-fold more resistant to antibiotics and to evade the action of the host’s immune system. For this reason, biofilm-related infections are very difficult to treat. To develop new strategies against biofilms, it is important to know the mechanisms involved in their formation. In this review, the different steps of biofilm formation in E. coli, the mechanisms of tolerance to antimicrobials and new compounds and strategies to combat biofilms are discussed

Análisis de la calidad del empleo de los universitarios : una aplicación al caso de Aragón

Resumen tomado de la publicaciónLas inversiones realizadas para mejorar los niveles educativos de una sociedad se justifican desde dos perspectivas: el enriquecimiento cultural de los individuos y de la sociedad y la adaptación y mejora en la inserción laboral de los titulados. En el caso de los egresados universitarios, la adecuada inserción implicará, entre otros aspectos, que obtengan un empleo adecuado a su nivel educativo, que exista una baja tasa de desempleo entre los mismos, etc. Tiene como objetivo analizar diversos aspectos de la inserción laboral de los egresados universitarios. De este modo, se analiza la calidad del empleo de los universitarios, a partir de aspectos como el posible desajuste en el nivel educativo existente en los egresados universitarios cuando acceden a un empleo, la temporalidad del mismo, e incluso la polivalencia intersectorial. Se realiza en el contexto de Aragón, y se llega a un análisis desagregado a nivel de titulación universitaria. Para alcanzar dicho objetivo se ha realizado un análisis de todos los contratos celebrados en Aragón durante los años 2005 y 2006 en los que han intervenido graduados universitarios de la Universidad de Zaragoza. Los resultados obtenidos muestran la existencia de importantes diferencias en los perfiles de inserción laboral de los egresados universitarios entre las titulaciones y áreas de conocimiento analizadas. Esta información es especialmente relevante en el contexto de adaptación de las titulaciones a las nuevas exigencias del Espacio Europeo de Educación Superior, en un momento en el que se abre el catálogo de titulaciones y las universidades podrán crear nuevos títulos que buscarán una conexión con el mercado de trabajo.NavarraUniversidad de Navarra. Biblioteca; 31080 Pamplona; +34948425600; +3494817731080; [email protected]