Dataset Information

Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections.

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.).

SUBMITTER: O'Dwyer K

PROVIDER: S-EPMC4291364 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections.

O'Dwyer Karen K Spivak Aaron T AT Ingraham Karen K Min Sharon S Holmes David J DJ Jakielaszek Charles C Rittenhouse Stephen S Kwan Alan L AL Livi George P GP Sathe Ganesh G Thomas Elizabeth E Van Horn Stephanie S Miller Linda A LA Twynholm Monique M Tomayko John J Dalessandro Marybeth M Caltabiano Madelyn M Scangarella-Oman Nicole E NE Brown James R JR

Antimicrobial agents and chemotherapy 20141027 1

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 ...[more]

PMID: 25348524

Similar Datasets

Project description:Background and Objectives. Numerous studies have been conducted to explore the epidemiological characteristics of urinary tract infections (UTI) and sepsis. However, there is still a lack of relevant bacteriological features and prognostic information regarding urosepsis based on bacteriological etiology. The current study aims to evaluate the bacterial etiology of complicated UTI (cUTI) and bacterial resistance to antibiotics and whether they present an intrinsic risk of developing urosepsis. Materials and Methods. A retrospective study was performed that included 102 patients who were diagnosed with cUTI and admitted to the urology department of the "Sfântul Apostol Andrei" County Emergency Clinical Hospital (GCH) from September 2019 to May 2022. Results. A considerable number of patients, n = 41 (40.2%), were diagnosed with multi drug-resistant (MDR) infection. Escherichia coli (E. coli) was identified as the prevailing pathogen, accounting for 51 patients. Klebsiella manifested itself as the subsequent causative agent in 27 instances. The presence of Enterococcus spp. infection was documented in 13 patients, whereas Pseudomonas emerged as the etiological perpetrator in the clinical context of 8 patients. The current study found a substantial prevalence of resistance to first-line antibiotics. The overall resistance rate was 74.5% for penicillin, 58.82% for trimethoprim-sulfamethoxazole and 49% for fluoroquinolones; cephalosporin resistance displayed an inverse correlation with antibiotic generation with fourth-generation cephalosporins exhibiting a resistance rate of 24.5%, and first-generation cephalosporins demonstrating a resistance rate of 35.29%. Conclusions. Age, comorbidities and indwelling urinary catheters are risk factors for developing MDR infections. While the intrinsic characteristics of the causative bacterial agent in cUTI may not be a risk factor for developing urosepsis, they can contribute to increased mortality risk. For empiric antibiotic treatment in patients with cUTI who are at a high risk of developing urosepsis and experiencing a potentially unfavorable clinical course, broad-spectrum antibiotic therapy is recommended. This may include antibiotics, such as amikacin, tigecycline, carbapenems and piperacillin-tazobactam.

Dataset Information

Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections.

Publications

Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets