Abstract
BackgroundThe 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. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP).MethodsA combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP.FindingsEBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin.InterpretationThis study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
Highlights
Urinary tract infections (UTI) are reported with a prevalence of more than 10% for women in the USA and are estimated to affect 150 million people worldwide each year [1,2]
We found Enterobacterales to be the predominant group of Gram-negative uropathogens, with 5456 (42.1%) Klebsiella pneumoniae and 5049 (39.0%) E. coli isolates deposited in the National Database of Antibiotic Resistant Organisms (NDARO) at the time of analysis
It was surprising to find the efficacious potency of EBL-1003 in vivo resembling the dose-response curve of gentamicin
Summary
Urinary tract infections (UTI) are reported with a prevalence of more than 10% for women in the USA and are estimated to affect 150 million people worldwide each year [1,2]. Gram-negative bacteria of the order Enterobacterales with Escherichia coli estimated to account for more than 80% of these [4,6] Pseudomonas aeruginosa represents another problematic and often multidrugresistant (MDR) uropathogen. 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.
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