Siderophore Conjugates\nof Daptomycin are Potent Inhibitors of Carbapenem Resistant Strains\nof <i>Acinetobacter baumannii</i>

Abstract

Development\nof resistance to antibiotics is a major medical problem. One approach\nto extending the utility of our limited antibiotic arsenal is to repurpose\nantibiotics by altering their bacterial selectivity. Many antibiotics\nthat are used to treat infections caused by Gram-positive bacteria\nmight be made effective against Gram-negative bacterial infections,\nif they could circumvent permeability barriers and antibiotic deactivation\nprocesses associated with Gram-negative bacteria. Herein, we report\nthat covalent attachment of the normally Gram-positive-only antibiotic,\ndaptomycin, with iron sequestering siderophore mimetics that are recognized\nby Gram-negative bacteria, provides conjugates that are active against\nvirulent strains of <i>Acinetobacter baumannii</i>, including\ncarbapenemase and cephalosporinase producers. The result is the generation\nof a new set of antibiotics designed to target bacterial infections\nthat have been designated as being of dire concern.