Abstract
Antibiotic resistance is a global health concern and a current threat to modern medicine and society. New strategies for antibiotic drug design and delivery offer a glimmer of hope in a currently limited pipeline of new antibiotics. One strategy involves conjugating iron-chelating microbial siderophores to an antibiotic or antimicrobial agent to enhance uptake and antibacterial potency. Cefiderocol (S-649266) is a promising cephalosporin–catechol conjugate currently in phase III clinical trials that utilizes iron-mediated active transport and demonstrates enhanced potency against multi-drug resistant (MDR) Gram-negative pathogens. Such molecules demonstrate that siderophore–antibiotic conjugates could be important future medicines to add to our antibiotic arsenal. This review is written in the context of the chemical design of siderophore–antibiotic conjugates focusing on the differing siderophore, linker, and antibiotic components that make up conjugates. We selected chemically distinct siderophore–antibiotic conjugates as exemplary conjugates, rather than multiple analogues, to highlight findings to date. The review should offer a general guide to the uninitiated in the molecular design of siderophore–antibiotic conjugates.
Highlights
Antimicrobial resistance, including antibiotic resistance, is a major threat to global human health and society at large [1]
Dolence et al reported the total synthesis of carbacephalosporin β-lactam antibiotics conjugated to tripeptides such as compound 8 attempting to mimic the iron chelating functionality of albomycin [22]
Milliner et al sought to gain selective antibacterial activity against S. aureus by conjugating a number of analogues of staphyloferrin A, which is a natural siderophore of S. aureus, to ciprofloxacin [39]
Summary
Antimicrobial resistance, including antibiotic resistance, is a major threat to global human health and society at large [1]. Cefiderocol, 5, utilizes ferric iron transport uptake in Gram-negative pathogens [14]; it induces susceptibility and enhanced killing against antibiotic resistant strains of Gram-negative pathogens, including Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, and Enterobacteriaceae [12]. Molecules such as Cefiderocol, 5, offer hope for the development of new siderophore–antibiotic conjugates as drugs to treat bacterial infections, including MDR bacteria.
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