SAR Studies Leading to the Identification of a Novel Series of Metallo-β-lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model

The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-β-lactamase (MBL) and serine-β-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new β-lactamase inhibitors to be used in conjunction with carbapenems and other β-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-β-lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem

Depolarization spatial variance as a cardiac dyssynchrony descriptor

Ventricular depolarization dispersion refers mainly to heterogeneity in interlead QRS durations. Here, we propose the spatial variance (SVd) to describe depolarization dispersion about a mean QRS morphology. We hypothesize that waveform changes can be more accurate than interval changes at measuring QRS heterogeneity, and less sensitive to delineation errors. To prove this, SVd was computed on 36 dyssyn-chrony patients either in sinus rhythm (SVdB) or under nHB (SVdHB), and on 32 control subjects with native conduction (SVdN). In the normal ECG, there are interlead sets that produce maximal (SVdNmax) and minimal (SVdNmin) spatial variance. In Baseline patients, SVdB significantly increased from controls in the minimal variance situation (p < 0.005), deviating one or more leads from the normal morphology (similar in all the ensemble) and consequently increasing the interlead distance. The opposite held for the maximal variance situation, where it was expected a wide span of morphologies in health, there was a tendency to stacking in morphologies at baseline (p<0.005). In both cases nHB induced QRS normalization, demonstrated by the return of SVdHB towards controls SVdN (p = NS). However, QRS narrowing not always accompanied morphological changes. The average rate of QRS normalization was 84% and 89% for SVdNmax and SVdNmin respectively while the rate of QRS narrowing equaled 71% in a multilead approach and performed worse than SVd at baseline-nHB separation. Ensembles with minimal interlead distance produced the best AUC values (aVR-V1, I-aVF-V6, I-II-aVF-V6). In conclusion, SVd may complement QRS width in the electrocardiographic assessment of dyssynchrony.Fil: Bonomini, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderón; ArgentinaFil: Ortega, Daniel F.. Clínica San Camilo; Argentina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Barja, Luis D.. Universidad Austral. Hospital Universitario Austral; Argentina. Clínica San Camilo; ArgentinaFil: Mangani, Nicolas. Clínica San Camilo; Argentina. Universidad Austral. Hospital Universitario Austral; ArgentinaFil: Arini, Pedro David. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderón; Argentin

Non-selective His bundle pacing with a biphasic waveform: enhancing septal resynchronization

Aims: His bundle pacing has shown to prevent detrimental effects from right ventricular apical pacing (RVA) and proved to resynchronize many conduction disturbances cases. However, the extent of His bundle pacing resynchronization is limited. An optimized stimulation waveform could expand this limit when implemented in His bundle pacing sets. In this work, we temporarily implemented RVA and Non-selective His bundle pacing with a biphasic anodal-first waveform (AF-nHB) and compared their effects against sinus rhythm (SR). Methods and results: Fifteen patients referred for electrophysiologic study with conduction disturbances, cardiomyopathy and ejection fraction below 35% were enrolled for the study. The following acute parameters were measured: QRS duration, left ventricular activation (RLVT), time of isovolumic contraction (IVCT), ejection fraction (EF), and dP/dtmax. QRS duration and RLVT decreased markedly under AF-nHB (SR: 169 ± 34 ms vs. nHB: 116 ± 31 ms, P < 0.0005) while RVA significantly increased QRS duration (SR: 169 ms vs. RVA: 198 ms, P < 0.05) and did not change RLVT (P = NS). Consistently, IVCT moderately decreased under AF-nHB (SR: 238 ms vs. RVA: 184 ms, P < 0.05 vs. SR) and dP/dtmax showed a 93.35 [mmHg] average increase under AF-nHB against SR. Also, T-wave inversions were observed during AF-nHB immediately after SR and RVA pacing suggesting the occurrence of cardiac memory. Conclusions: AF-nHB corrected bundle branch blocks in patients with severe conduction disturbances, even in those with dilated cardiomiopathy, outstanding from RVA. Also, the occurrence of cardiac memory during AF-nHB turned up as an observational finding of this study.Fil: Ortega, Daniel F.. Clínica San Camilo; Argentina. Hospital Universitario Austral; ArgentinaFil: Barja, Luis D.. Clínica San Camilo; Argentina. Hospital Universitario Austral; ArgentinaFil: Logarzo, Emilio. Clínica San Camilo; Argentina. Hospital Universitario Austral; ArgentinaFil: Mangani, Nicolas. Clínica San Camilo; Argentina. Hospital Universitario Austral; ArgentinaFil: Paolucci, Analia. Clínica San Camilo; Argentina. Hospital Universitario Austral; ArgentinaFil: Bonomini, Maria Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderón; Argentina. Universidad de Buenos Aires. Facultad de Ingeniería; Argentin

Abordaje eléctrico para mejorar la activación ventricular izquierda durante estimulación del ventrículo derecho

Coronary sinus mapping is commonly used to evaluate left atrial activation. Herein, we propose to use it to assess which right ventricular pacing modality produces the shortest left ventricular activation times (R-LVtime) and the narrowest QRS widths. Three study groups were defined: 54 controls without intraventricular conduction disturbances; 15 patients with left bundle branch block, and 15 patients with right bundle branch block. Left ventricular activation times and QRS widths were evaluated among groups under sinus rhythm, right ventricular apex, right ventricular outflow tract and high output septal zone (SEPHO). Left ventricular activation time was measured as the time elapsed from the surface QRS onset to the most distal left ventricular deflection recorded at coronary sinus. During the above stimulation modalities, coronary sinus mapping reproduced electrical differences that followed mechanical differences measured by tissue doppler imaging. Surprisingly, 33% of the patients with left bundle branch block displayed an early left ventricular activation time, suggesting that these patients would not benefit from resynchronization therapy. SEPHO improved QRS widths and left ventricular activation times in all groups, especially in patients with left bundle branch block, in whom these variables became similar to controls. Left ventricular activation time could be useful to search the optimum pacing site and would also enable detection of non-responders to cardiac resynchronization therapy. Finally, SEPHO resulted the best pacing modality, because it narrowed QRS-complexes and shortened left ventricular activations of patients with left bundle branch block and preserved the physiological depolarization of controls.El mapeo del seno coronario se utiliza comúnmente para evaluar la activación de la aurícula izquierda. Aquí, investigamos su utilidad para evaluar qué modalidad de estimulación ventricular derecha produce los menores tiempos de activación ventricular izquierda (R-LVtime). Se definieron tres grupos: 54 controles; 15 pacientes con bloqueo de rama izquierda y 15 con bloqueo de rama derecha. El ancho de QRS y los tiempos de activación fueron evaluados en cada grupo bajo las siguientes modalidades: ritmo sinusal, ápex del ventrículo derecho, tracto de salida del ventrículo derecho y alta salida en septum (SEPHO). El R-LVtime se midió como el tiempo transcurrido desde el inicio del QRS de superficie y la deflexión ventricular izquierda más distal del seno coronario. Durante las distintas modalidades de estimulación, el mapeo del seno coronario reprodujo diferencias eléctricas acompañadas por diferencias mecánicas que fueron evaluadas mediante Tissue Doppler Imaging. El 33% de los pacientes con bloqueo de rama izquierda mostró R-LVtime tempranos, lo que sugiere que estos pacientes no se beneficiarían con terapia de resincronización. SEPHO mejoró el ancho de QRS y el R-LVtime de todos los grupos, especialmente en los pacientes con bloqueo de rama izquierda. En conclusión, el R-LVtime serviría para identificar el sitio óptimo de estimulación y permitiría detectar ciertos no respondedores a la terapia de resincronización. Además, el SEPHO resultó la mejor modalidad de estimulación porque estrechó el QRS y acortó el R-LVtime de los pacientes con bloqueo de rama izquierda pero no alteró la despolarización fisiológica de los controles.Fil: Bonomini, Maria Paula. Universidad de Buenos Aires. Facultad de Ingenieria. Instituto de Ingeniería Biomédica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Argentino de Matemática Alberto Calderon; ArgentinaFil: Ortega, Daniel Felipe. Hospital Universitario Austral; ArgentinaFil: Barja, Luis Dante. Hospital Universitario Austral; ArgentinaFil: Mangani, Nicolas. Hospital Universitario Austral; ArgentinaFil: Paolucci, Analia. Hospital Universitario Austral; ArgentinaFil: Logarzo, Emilio. Hospital Universitario Austral; Argentin

Discovery of ANT3310, a Novel Broad-Spectrum Serine β-Lactamase Inhibitor of the Diazabicyclooctane Class, Which Strongly Potentiates Meropenem Activity against Carbapenem-Resistant Enterobacterales and Acinetobacter baumannii

The diazabicyclooctanes (DBOs) are a class of serine β-lactamase (SBL) inhibitors that use a strained urea moiety as the warhead to react with the active serine residue in the active site of SBLs. The first in-class drug, avibactam, as well as several other recently approved DBOs (e.g., relebactam) or those in clinical development (e.g., nacubactam and zidebactam) potentiate activity of β-lactam antibiotics, to various extents, against carbapenem-resistant Enterobacterales (CRE) carrying class A, C, and D SBLs; however, none of these are able to rescue the activity of β-lactam antibiotics against carbapenem-resistant Acinetobacter baumannii (CRAB), a WHO “critical priority pathogen” producing class D OXA-type SBLs. Herein, we describe the chemical optimization and resulting structure–activity relationship, leading to the discovery of a novel DBO, ANT3310, which uniquely has a fluorine atom replacing the carboxamide and stands apart from the current DBOs in restoring carbapenem activity against OXA-CRAB as well as SBL-carrying CRE pathogens.Peer reviewe

Front Microbiol

Saccharomyces cerevisiae is by far the most widely used yeast in oenology. However, during the last decade, several other yeasts species has been purposed for winemaking as they could positively impact wine quality. Some of these non-conventional yeasts (Torulaspora delbrueckii, Metschnikowia pulcherrima, Pichia kluyveri, Lachancea thermotolerans, etc.) are now proposed as starters culture for winemakers in mixed fermentation with S. cerevisiae, and several others are the subject of various studies (Hanseniaspora uvarum, Starmerella bacillaris, etc.). Along with their biotechnological use, the knowledge of these non-conventional yeasts greatly increased these last 10 years. The aim of this review is to describe the last updates and the current state-of-art of the genetics of non-conventional yeasts (including S. uvarum, T. delbrueckii, S. bacillaris, etc.). We describe how genomics and genetics tools provide new data into the population structure and biodiversity of non-conventional yeasts in winemaking environments. Future challenges will lie on the development of selection programs and/or genetic improvement of these non-conventional species. We discuss how genetics, genomics and the advances in next-generation sequencing will help the wine industry to develop the biotechnological use of non-conventional yeasts to improve the quality and differentiation of wines