Trial reportAntimicrobial agents and chemotherapy2015
Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections.
Trial report in Antimicrobial agents and chemotherapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 57 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Randomised, Double-blind, Dose-finding, Multicenter Study of the Safety, Tolerability, and Efficacy of GSK2251052 Therapy Compared to Imipenem-cilastatin in the Treatment of Adult Subjects With Febrile Complicated Lower Urinary Tract Infections and Acute Pyelonephritis
A Study to Assess the Safety, Tolerability and Preliminary Efficacy of GSK2251052 in the Treatment of Complicated Intra-abdominal Infection in Adults
Who cites it
57 citing papers in PubMed.
- Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota.Antimicrobial agents and chemotherapy · 2019Trial
- Antibiotic-producing microorganisms: taxonomic diversity, screening strategies, and emerging and underexploited antibacterial targets.Archives of microbiology · 2026Review
- Predicting resistance evolution to guide antibiotic development.Nature reviews. Microbiology · 2026Review
- The ZN domain acts as a dynamic switch coordinating multiple-step aminoacylation in bacterial leucyl-tRNA synthetase.Nucleic acids research · 2026Article
- Repurposing epetraborole to combatAntimicrobial agents and chemotherapy · 2026Article
- Preclinical evaluation of epetraborole in the hollow fibre system model of Mycobacterium abscessus lung disease.The Journal of antimicrobial chemotherapy · 2026Article
- Global health perspectives on antibacterial drug discovery and the preclinical pipeline.Nature reviews. Microbiology · 2025Review
- Antibiotics re-booted-time to kick back against drug resistance.npj antimicrobials and resistance · 2025Review
- ESKAPE pathogens rapidly develop resistance against antibiotics in development in vitro.Nature microbiology · 2025Article
- A Review of Antibacterial Candidates with New Modes of Action.ACS infectious diseases · 2024Review
- In Vitro Resistance-Predicting Studies and In Vitro Resistance-Related Parameters-A Hit-to-Lead Perspective.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Laboratory Evolution of Antimicrobial Resistance in Bacteria to Develop Rational Treatment Strategies.Antibiotics (Basel, Switzerland) · 2024Review
- Unrealized targets in the discovery of antibiotics for Gram-negative bacterial infections.Nature reviews. Drug discovery · 2023Review
- Antibiotics in the clinical pipeline as of December 2022.The Journal of antibiotics · 2023Review
- DS86760016, a Leucyl-tRNA Synthetase Inhibitor, Is Active against Mycobacterium abscessus.Antimicrobial agents and chemotherapy · 2023Article
- A Leucyl-tRNA Synthetase Inhibitor with Broad-Spectrum Anti-Mycobacterial Activity.Antimicrobial agents and chemotherapy · 2023Article
- Loss of allosteric regulation in α-isopropylmalate synthase identified as an antimicrobial resistance mechanism.npj antimicrobials and resistance · 2023Article
- A Novel Leucyl-tRNA Synthetase Inhibitor, MRX-6038, Expresses Anti-Mycobacterium abscessus ActivityAntimicrobial agents and chemotherapy · 2022Article
- Leaks in the Pipeline: a Failure Analysis of Gram-Negative Antibiotic Development from 2010 to 2020.Antimicrobial agents and chemotherapy · 2022Review
- Penetration of Antibacterial Agents into Pulmonary Epithelial Lining Fluid: An Update.Clinical pharmacokinetics · 2022Review
Corrections and comments
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Authors and funding
19 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GSK2251052, a novel leucyl-tRNA synthetase (LeuRS) inhibitor, was in development for the treatment of infections caused by multidrug-resistant Gram-negative pathogens. In a phase II study (study LRS114688) evaluating the efficacy of GSK2251052 in complicated urinary tract infections, resistance developed very rapidly in 3 of 14 subjects enrolled, with ≥32-fold increases in the GSK2251052 MIC of the infecting pathogen being detected. A fourth subject did not exhibit the development of resistance in the baseline pathogen but posttherapy did present with a different pathogen resistant to GSK2251052. Whole-genome DNA sequencing of Escherichia coli isolates collected longitudinally from two study LRS114688 subjects confirmed that GSK2251052 resistance was due to specific mutations, selected on the first day of therapy, in the LeuRS editing domain. Phylogenetic analysis strongly suggested that resistant Escherichia coli isolates resulted from clonal expansion of baseline susceptible strains. This resistance development likely resulted from the confluence of multiple factors, of which only some can be assessed preclinically. Our study shows the challenges of developing antibiotics and the importance of clinical studies to evaluate their effect on disease pathogenesis. (These studies have been registered at ClinicalTrials.gov under registration no. NCT01381549 for the study of complicated urinary tract infections and registration no. NCT01381562 for the study of complicated intra-abdominal infections.).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.