Amino acid competition shapes gut carriage.

Antimicrobial resistance is an urgent threat to human health. Asymptomatic colonization is often critical for persistence of antimicrobial-resistant pathogens. Gut colonization by the antimicrobial-resistant priority pathogen is associated with increased risk of clinical infection.

Salmonella re-engineers the intestinal environment to break colonization resistance in the presence of a compositionally intact microbiota.

The gut microbiota prevents harmful microbes from entering the body, a function known as colonization resistance. The enteric pathogen Salmonella enterica serovar (S.) Typhimurium uses its virulence factors to break colonization resistance through unknown mechanisms.

Epithelial hypoxia maintains colonization resistance against Candida albicans.

Antibiotic treatment promotes the outgrowth of intestinal Candida albicans, but the mechanisms driving this fungal bloom remain incompletely understood. We identify oxygen as a resource required for post-antibiotic C. albicans expansion.

High fat intake sustains sorbitol intolerance after antibiotic-mediated Clostridia depletion from the gut microbiota.

Carbohydrate intolerance, commonly linked to the consumption of lactose, fructose, or sorbitol, affects up to 30% of the population in high-income countries. Although sorbitol intolerance is attributed to malabsorption, the underlying mechanism remains unresolved. Here, we show that a history of antibiotic exposure combined with high fat intake triggered long-lasting sorbitol intolerance in mice by reducing Clostridia abundance, which impaired microbial sorbitol catabolism.

Dose selection for a phase III study evaluating gepotidacin (GSK2140944) in the treatment of uncomplicated urogenital gonorrhoea.

Background: Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and is active against most strains of (). Phase II data suggested higher exposures were needed for efficacy and to suppress resistance development. A translational approach using in vitro pharmacokinetic/pharmacodynamic (PK/PD) and clinical data was used to select a gepotidacin dose for a phase III study.

Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants.

Background: Uncomplicated urinary tract infections (uUTIs) are among the most common community-acquired infections for women worldwide. Treatment options are increasingly limited by antibiotic resistance; novel oral antibiotics are urgently needed. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial deoxyribonucleic acid (DNA) replication by a distinct mechanism of action, which confers activity against most strains of target pathogens, such as Escherichia coli and Staphylococcus saprophyticus, including those resistant to current antibiotics.

Pharmacokinetics, safety, and tolerability of gepotidacin administered as single or repeat ascending doses, in healthy adults and elderly subjects.

Gepotidacin, a novel, first-in-class triazaacenaphthylene antibiotic, inhibits bacterial DNA replication by a distinct mechanism of action. We report the pharmacokinetics (PKs), safety, and tolerability of gepotidacin following single or multiple ascending doses. Studies 1 and 2 were randomized, single-blind, placebo-controlled trials in healthy adults aged 18-60 years, who received single (study 1 [NCT02202187]; 100-3000 mg) or repeat (study 2 [NCT01706315]; 400 mg twice daily to 2000 mg thrice daily) ascending doses of gepotidacin.

Dose Selection for Phase III Clinical Evaluation of Gepotidacin (GSK2140944) in the Treatment of Uncomplicated Urinary Tract Infections.

Antibiotics are the current standard-of-care treatment for uncomplicated urinary tract infections (uUTIs). However, increasing rates of bacterial antibiotic resistance necessitate novel therapeutic options. Gepotidacin is a first-in-class triazaacenaphthylene antibiotic that selectively inhibits bacterial DNA replication by interaction with the bacterial subunits of DNA gyrase (GyrA) and topoisomerase IV (ParC).

Pharmacokinetics of Oral Formulations of Gepotidacin (GSK2140944), a Triazaacenaphthylene Bacterial Type II Topoisomerase Inhibitor, in Healthy Adult and Adolescent Participants.

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that may provide a new treatment option for antibiotic-resistant pathogens. Two pharmacokinetic evaluations of oral gepotidacin are presented: a relative bioavailability study that guided formulation development, followed by an adult and adolescent study of the final formulation. In the relative bioavailability study, after gepotidacin administration to 26 healthy adults as free-base roller-compacted (RC) tablets, free-base high-shear wet granulation (HSWG) tablets, and mesylate salt reference capsules, the RC tablet exposure ratios and 90% confidence intervals (CIs) were within the 0.

The metabolic footprint of Clostridia and Erysipelotrichia reveals their role in depleting sugar alcohols in the cecum.

Background: The catabolic activity of the microbiota contributes to health by aiding in nutrition, immune education, and niche protection against pathogens. However, the nutrients consumed by common taxa within the gut microbiota remain incompletely understood.

Methods: Here we combined microbiota profiling with an un-targeted metabolomics approach to determine whether depletion of small metabolites in the cecum of mice correlated with the presence of specific bacterial taxa.

High-fat diet-induced colonocyte dysfunction escalates microbiota-derived trimethylamine -oxide.

A Western-style, high-fat diet promotes cardiovascular disease, in part because it is rich in choline, which is converted to trimethylamine (TMA) by the gut microbiota. However, whether diet-induced changes in intestinal physiology can alter the metabolic capacity of the microbiota remains unknown. Using a mouse model of diet-induced obesity, we show that chronic exposure to a high-fat diet escalates choline catabolism by altering intestinal epithelial physiology.

Comparison between physiologically based pharmacokinetic and population pharmacokinetic modelling to select paediatric doses of gepotidacin in plague.

Aims: To develop physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models to predict effective doses of gepotidacin in paediatrics for the treatment of pneumonic plague (Yersinia pestis).

Methods: A gepotidacin PBPK model was constructed using a population-based absorption, distribution, metabolism and excretion simulator, Simcyp®, with physicochemical and in vitro data, optimized with clinical data from a dose-escalation intravenous (IV) study and a human mass balance study. A PopPK model was developed with pooled PK data from phase 1 studies with IV gepotidacin in healthy adults.

Hydration effect on kidney function and serum electrolyte in children with tumor lysis syndrome (TLS) and risk of TLS.

Objectives: Tumor lysis syndrome (TLS) is a life-threatening oncology emergency disorder, which may cause acute kidney injury (AKI), arrhythmias, seizures, and sudden death. Hydration is used to prevent TLS in medium-high risk patients, and treatment in TLS patients. According to the pediatric protocol in Dr.

5-Aminosalicylic Acid Ameliorates Colitis and Checks Dysbiotic Escherichia coli Expansion by Activating PPAR-γ Signaling in the Intestinal Epithelium.

5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a widely used first-line medication for the treatment of ulcerative colitis, but its anti-inflammatory mechanism is not fully resolved. Here, we show that 5-ASA ameliorates colitis in dextran sulfate sodium (DSS)-treated mice by activating PPAR-γ signaling in the intestinal epithelium. DSS-induced colitis was associated with a loss of epithelial hypoxia and a respiration-dependent luminal expansion of , which could be ameliorated by treatment with 5-ASA.

Pharmacokinetics of Gepotidacin in Subjects With Normal Hepatic Function and Hepatic Impairment.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. This phase 1 nonrandomized, open-label, multicenter, 2-part study evaluated the pharmacokinetics, safety, and tolerability of oral gepotidacin 1500 mg in 3 different hepatic settings (normal, moderate impairment, and severe impairment). Gepotidacin was safe and generally tolerated in all subjects.

Anaerobic Respiration of NOX1-Derived Hydrogen Peroxide Licenses Bacterial Growth at the Colonic Surface.

The colonic microbiota exhibits cross-sectional heterogeneity, but the mechanisms that govern its spatial organization remain incompletely understood. Here we used Citrobacter rodentium, a pathogen that colonizes the colonic surface, to identify microbial traits that license growth and survival in this spatial niche. Previous work showed that during colonic crypt hyperplasia, type III secretion system (T3SS)-mediated intimate epithelial attachment provides C.

High-Fat Diet and Antibiotics Cooperatively Impair Mitochondrial Bioenergetics to Trigger Dysbiosis that Exacerbates Pre-inflammatory Bowel Disease.

The clinical spectra of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) intersect to form a scantily defined overlap syndrome, termed pre-IBD. We show that increased Enterobacteriaceae and reduced Clostridia abundance distinguish the fecal microbiota of pre-IBD patients from IBS patients. A history of antibiotics in individuals consuming a high-fat diet was associated with the greatest risk for pre-IBD.

Pharmacokinetics of Gepotidacin in Renal Impairment.

Gepotidacin is a novel triazaacenaphthylene bacterial topoisomerase inhibitor. In this phase 1, nonrandomized, open-label, parallel-group, multicenter, multipart study, the pharmacokinetics, safety, and tolerability of a single intravenous (IV) dose of gepotidacin 750 mg over 2 hours were evaluated in subjects with normal renal function, in those with moderate and severe renal impairment, and in end-stage renal disease (ESRD) on and not on dialysis. Administration of IV gepotidacin 750 mg was safe and generally tolerated in the study subjects.

Phase 2a Pharmacokinetic, Safety, and Exploratory Efficacy Evaluation of Oral Gepotidacin (GSK2140944) in Female Participants with Uncomplicated Urinary Tract Infection (Acute Uncomplicated Cystitis).

Gepotidacin, a triazaacenaphthylene bacterial type II topoisomerase inhibitor, is in development for treatment of uncomplicated urinary tract infection (uUTI). This phase 2a study in female participants with uUTI evaluated the pharmacokinetics (primary objective), safety, and exploratory efficacy of gepotidacin. Eligible participants ( = 22) were confined to the clinic at baseline, received oral gepotidacin at 1,500 mg twice daily for 5 days (on-therapy period; days 1 to 5), and returned to the clinic for test-of-cure (days 10 to 13) and follow-up (day 28 ± 3) visits.

Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections.

A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12 h [q12h], 1,000 mg q12h, and 1,000 mg every 8 h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines.

Increased Epithelial Oxygenation Links Colitis to an Expansion of Tumorigenic Bacteria.

Intestinal inflammation is a risk factor for colorectal cancer formation, but the underlying mechanisms remain unknown. Here, we investigated whether colitis alters the colonic microbiota to enhance its cancer-inducing activity. Colitis increased epithelial oxygenation in the colon of mice and drove an expansion of within the gut-associated microbial community through aerobic respiration.

Dysbiosis: from fiction to function.

Advances in data collection technologies reveal that an imbalance (dysbiosis) in the composition of host-associated microbial communities (microbiota) is linked to many human illnesses. This association makes dysbiosis a central concept for understanding how the human microbiota contributes to health and disease. However, it remains problematic to define the term dysbiosis by cataloguing microbial species names.

omu, a Metabolomics Count Data Analysis Tool for Intuitive Figures and Convenient Metadata Collection.

Metabolomics is a powerful tool for measuring the functional output of the microbiota. Currently, there are few established workflows for analysis downstream of metabolite identification. Here, we introduce omu, an R package designed for assigning compound hierarchies and linking compounds to corresponding enzyme and gene annotations for organisms of interest.