Antimicrobial Resistance and Novel Antibiotic Development

Abstract

Antimicrobial resistance (AMR) constitutes a global health emergency, with the WHO ESKAPE pathogens - Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species -- collectively responsible for the majority of multidrug-resistant (MDR) nosocomial infections. This study systematically characterised the resistance mechanisms and evaluated novel antibiotic candidates against a panel of 180 MDR clinical isolates spanning all six ESKAPE species, collected from six European tertiary hospitals between 2019 and 2022. Whole-genome sequencing (WGS) identified resistance gene carriage and resistome profiles; minimum inhibitory concentrations (MICs) were determined for six novel antibiotic candidates -- cefiderocol (siderophore cephalosporin), omadacycline (aminomethylcycline tetracycline), ceftazidime-avibactam (beta-lactam/BLI), imipenem-relebactam, zoliflodacin (spiropyrimidinetrione), and gepotidacin (triazaacenaphthylene) -- alongside five comparators. Cefiderocol demonstrated the broadest activity, achieving MIC90 values within the susceptible breakpoint for all six ESKAPE species including metallo-beta-lactamase (MBL)-producing isolates (MIC90 = 4 µg/mL, susceptibility 91.4%). Ceftazidime-avibactam was highly active against KPC-producing K. pneumoniae (MIC90 = 2 µg/mL, susceptibility 94.8%) but inactive against MBL-producers. WGS resistome analysis identified blaKPC-2, blaNDM-1, blaOXA-48, and mcr-1 as the most prevalent resistance determinants. Resistance mechanism clustering revealed four distinct resistome archetypes with differential susceptibility profiles, providing a molecular framework for precision antibiotic selection in MDR infections