Biscatecholate–Monohydroxamate Mixed Ligand Siderophore–Carbacephalosporin Conjugates are Selective Sideromycin Antibiotics that Target Acinetobacter baumannii

Abstract

Chemical syntheses and biological evaluation of biscatecholate-monohydroxamate mixed ligand sideromycins utilizing the carbacephalosporin β-lactam antibiotic loracarbef and the fluoroquinolone antibiotic ciprofloxacin are described. The mixed ligand β-lactam sideromycin (1b) had remarkably selective and extremely potent antibacterial activity against the Gram-negative pathogen Acinetobacter baumannii ATCC 17961 (MIC = 0.0078 μM). The antibacterial activity of the β-lactam sideromycin was inversely related to the iron(III) concentration in the testing media and was antagonized by the presence of the competing parent siderophore. These data suggested that active transport of the mixed ligand β-lactam sideromycin across the outer cell membrane of A. baumannii via siderophore-uptake pathways was responsible for the selective and potent antibacterial activity.