Siderophore Conjugates of Daptomycin are Potent Inhibitors of Carbapenem Resistant Strains of Acinetobacter baumannii

Abstract

Development of resistance to antibiotics is a major medical problem. One approach to extending the utility of our limited antibiotic arsenal is to repurpose antibiotics by altering their bacterial selectivity. Many antibiotics that are used to treat infections caused by Gram-positive bacteria might be made effective against Gram-negative bacterial infections, if they could circumvent permeability barriers and antibiotic deactivation processes associated with Gram-negative bacteria. Herein, we report that covalent attachment of the normally Gram-positive-only antibiotic, daptomycin, with iron sequestering siderophore mimetics that are recognized by Gram-negative bacteria, provides conjugates that are active against virulent strains of Acinetobacter baumannii, including carbapenemase and cephalosporinase producers. The result is the generation of a new set of antibiotics designed to target bacterial infections that have been designated as being of dire concern.

A Siderophore Analog of Fimsbactin from Acinetobacter Hinders Growth of the Phytopathogen Pseudomonas syringae and Induces Systemic Priming of Immunity in Arabidopsis thaliana

“…The synthetic siderophores, i.e., the fimsbactin analog (SID) [ 22 ], and the bis-catechol (CAT) [ 24 ] were generously provided by Hsiri Therapeutics (Media, PA). The chemical structures of fimsbactin and myxochelin A [ 23 ], and those of their synthetic analogs SID and CAT, respectively, are presented in Figure 1 .…”

Repurposing approved drugs on the pathway to novel therapies

“…Similarly, small structural changes may completely alter the spectrum of activity of an antibiotic. Conjugation of daptomycin, an antibiotic targeting Gram‐positive bacteria, with an iron‐binding siderophore mimetic generated a new series of antibiotics that could penetrate the cell wall of Gram‐negative, antibiotic‐resistant strains of Acinetobacter baumannii …”

Drug delivery systems designed to overcome antimicrobial resistance

“…59 siderophores or siderophore mimics. [78][79][80] Antibiotics from other classes, including ciprofloxacin, 81 spiramycin, 82 vancomycin, 83 norfloxacin, 84,85 and daptomycin 86,87 have also been conjugated with siderophores. Synthetic siderophore-ATB conjugates have been reported to enhance the uptake of the drugs, thus boosting and/or expanding the effectiveness of common ATBs.…”

“…Gram-positive and Gram-negative bacteria by mainly disrupting the bacterial cell membrane as well as the adherent biofilms. 215 (87) also demonstrated a potential anti-inflammatory effect through the suppression of LPS-induced proinflammatory cytokines. 215 In a recent study, Gomarasca et al 200 α1H (91) and α2H (92).…”

“…(87) also exhibited a potent in vivo ATB activity against Salmonella enteritidis residing inside Caenorhabditis elegans worms, and displayed a lowF I G U R E 1 6 Kanamycin-antimicrobial peptide conjugates and the disulfide cleavage in intracellular reducing environment 211 T A B L E 11 Antimicrobial activity of the P14LRR-kanamycin conjugates and their parent components , minimal inhibitory concentration; n.d., not determined. a MIC in µM, in vitro.…”