Repurposing zidovudine and 5-fluoro-2'-deoxyuridine as antibiotic drugs made possible by synergy with both trimethoprim and the mitochondrial toxicity-reducing agent uridine.

Objectives: The increasing frequency of antibiotic-resistant bacterial infections is a major public health challenge, and new antibiotic drugs are urgently needed. A rapid solution to the problem is to repurpose clinically approved compounds with antibacterial properties, such as the nucleoside analogues zidovudine (azidothymidine) or 5-fluoro-2'-deoxyuridine. Here we report the in vitro and in vivo antibacterial properties of double and triple combinations of azidothymidine or 5-fluoro-2'-deoxyuridine with uridine and/or trimethoprim.

Model-informed drug development for antimicrobials: translational pharmacokinetic-pharmacodynamic modelling of apramycin to facilitate prediction of efficacious dose in complicated urinary tract infections.

Objectives: The use of mouse models of complicated urinary tract infection (cUTI) has usually been limited to a single timepoint assessment of bacterial burden. Based on longitudinal in vitro and in vivo data, we developed a pharmacokinetic-pharmacodynamic (PKPD) model to assess the efficacy of apramycin, a broad-spectrum aminoglycoside antibiotic, in mouse models of cUTI.

Methods: Two Escherichia coli strains were studied (EN591 and ATCC 700336).

Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors.

New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity.

Quantifying combined effects of colistin and ciprofloxacin against Escherichia coli in an in silico pharmacokinetic-pharmacodynamic model.

Co-administering a low dose of colistin (CST) with ciprofloxacin (CIP) may improve the antibacterial effect against resistant Escherichia coli, offering an acceptable benefit-risk balance. This study aimed to quantify the interaction between ciprofloxacin and colistin in an in silico pharmacokinetic-pharmacodynamic model from in vitro static time-kill experiments (using strains with minimum inhibitory concentrations, MIC 0.023-1 mg/L and MIC 0.

The Impact of Microvascular Resistance Reserve on the Outcome of Patients With STEMI.

Background: Microvascular resistance reserve (MRR) can characterize coronary microvascular dysfunction (CMD); however, its prognostic impact in ST-segment elevation myocardial infarction (STEMI) patients remains undefined.

Objectives: This study sought to investigate the prevalence of CMD in STEMI patients and to elucidate the prognostic performance of MRR.

Methods: This prospective cohort study enrolled 210 STEMI patients with multivessel disease who underwent successful revascularization and returned at 3 months for coronary physiology assessments with bolus thermodilution.

Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models.

Background: The aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed.

Methods: The resistance gene annotations of 40 888 blood-culture isolates were analysed.

Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria.

Here, we describe the identification of an antibiotic class acting via LpxH, a clinically unexploited target in lipopolysaccharide synthesis. The lipopolysaccharide synthesis pathway is essential in most Gram-negative bacteria and there is no analogous pathway in humans. Based on a series of phenotypic screens, we identified a hit targeting this pathway that had activity on efflux-defective strains of .

Impact of Bariatric Surgery on Left Ventricular Structure and Function.

Background: Obesity leads to an increased risk of cardiovascular disease morbidity and death, including heart failure. Bariatric surgery has been proven to be the most effective long-term weight management treatment. This study investigated the changes in cardiac structure and function after bariatric surgery, including left ventricular global longitudinal strain.

Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against and .

We have developed compounds with a promising activity against and , which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor , we identified compound , featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from and , a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of in complex with GyrB24 and ()- in complex with GyrB23 and GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit.

Effect of a Run-In Period on Estimated Treatment Effects in Cardiovascular Randomized Clinical Trials: A Meta-Analytic Review.

Background A run-in period may increase adherence to intervention and reduce loss to follow-up. Whether use of a run-in period affects the magnitude of treatment effects is unknown. Methods and Results We conducted a meta-analysis comparing treatment effects from 11 systematic reviews of cardiovascular prevention trials using a run-in period with matched trials not using a run-in period.

Expanding utility of cardiac computed tomography in infective endocarditis: A contemporary review.

There is increasing evidence on the utility of cardiac computed tomography (CCT) in infective endocarditis (IE) to investigate the valvular pathology, the extra-cardiac manifestations of IE and pre-operative planning. CCT can assist in the diagnosis of perivalvular complications, such as pseudoaneurysms and abscesses, and can help identify embolic events to the lungs or systemic vasculature. CCT has also been shown to be beneficial in the pre-operative planning of patients by delineating the coronary artery anatomy and the major cardiovascular structures in relation to the sternum.

Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents.

Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of models that mimic clinical infection, translational challenges remain high.

Expert workshop summary: Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections.

The rise in antimicrobial resistance (AMR), and increase in treatment-refractory AMR infections, generates an urgent need to accelerate the discovery and development of novel anti-infectives. Preclinical animal models play a crucial role in assessing the efficacy of novel drugs, informing human dosing regimens and progressing drug candidates into the clinic. The Innovative Medicines Initiative-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium is establishing a validated and globally harmonized preclinical model to increase reproducibility and more reliably translate results from animals to humans.

Evolution of Bacterial Interspecies Hybrids with Enlarged Chromosomes.

Conjugation driven by a chromosomally integrated F-plasmid (high frequency of recombination strain) can create bacteria with hybrid chromosomes. Previous studies of interspecies hybrids have focused on hybrids in which a region of donor chromosome replaces an orthologous region of recipient chromosome leaving chromosome size unchanged. Very little is known about hybrids with enlarged chromosomes, the mechanisms of their creation, or their subsequent trajectories of adaptative evolution.

Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia.

Objectives: New drugs and methods to efficiently fight carbapenem-resistant gram-negative pathogens are sorely needed. In this study, we characterized the preclinical pharmacokinetics (PK) and pharmacodynamics of the clinical stage drug candidate apramycin in time kill and mouse lung infection models. Based on in vitro and in vivo data, we developed a mathematical model to predict human efficacy.

Positive Selection during Niche Adaptation Results in Large-Scale and Irreversible Rearrangement of Chromosomal Gene Order in Bacteria.

Analysis of bacterial genomes shows that, whereas diverse species share many genes in common, their linear order on the chromosome is often not conserved. Whereas rearrangements in gene order could occur by genetic drift, an alternative hypothesis is rearrangement driven by positive selection during niche adaptation (SNAP). Here, we provide the first experimental support for the SNAP hypothesis.

Synthesis and Biological Evaluation of Quinolinyl Pyrimidines Targeting Type II NADH-Dehydrogenase (NDH-2).

Type II NADH dehydrogenase (NDH-2) is an essential component of electron transfer in many microbial pathogens but has remained largely unexplored as a potential drug target. Previously, quinolinyl pyrimidines were shown to inhibit NDH-2, as well as the growth of the bacteria [Shirude, P. S.

Rilonacept for the treatment of recurrent pericarditis.

Introduction: Recurrent pericarditis (RP) is a debilitating disease that has an underlying autoinflammatory pathophysiology mediated by cytokine interleukin (IL)-1. Rilonacept, a recombinant dimeric fusion protein that blocks IL-1α and IL-1β signaling has emerged as a valuable therapeutic option of RP. Rilonacept has been evaluated in Phase 2 and 3 clinical trials and was recently approved for RP treatment.

Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis.

Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided.

Antibacterial sulfonimidamide-based oligopeptides as type I signal peptidase inhibitors: Synthesis and biological evaluation.

Oligopeptide boronates with a lipophilic tail are known to inhibit the type I signal peptidase in E. coli, which is a promising drug target for developing novel antibiotics. Antibacterial activity depends on these oligopeptides having a cationic modification to increase their permeation.

Chromosomal Location Determines the Rate of Intrachromosomal Homologous Recombination in Salmonella.

Homologous recombination is an important mechanism directly involved in the repair, organization, and evolution of prokaryotic and eukaryotic chromosomes. We developed a system, based on two genetic cassettes, that allows the measurement of recombinational repair rates between different locations on the chromosome. Using this system, we analyzed 81 different positional combinations throughout the chromosome to answer the question of how the position and orientation of sequences affect intrachromosomal homologous recombination.