![]() and guided our design strategy to introduce an iron chelating moiety. The X-ray structure of compound 1 ((2 R)-1-piperidine-2-carboxylic acid) in complex with NDM-1 has been published by Ma et al. and us have previously reported on D-pipecolic acid-based MBL inhibitors. In this study, we report the incorporation of catechol moieties into thiol-based MBL inhibitors. Design of Siderophore-Containing MBL Inhibitors In this study we applied the sideromycin concept to thiol-based MBL inhibitors by integrating catechol moieties. ![]() This combination makes cifederocol a highly effective antibiotic active against multi-resistant pathogens. Cifederocol is a synthetic sideromycin that comprises a cephalosporin antibiotic linked to a catechol moiety, which is responsible for iron chelation. Various combinations of siderophores and antibiotic agents have been reported so far, ultimately leading to the recent approval of cifederocol ( Figure 1). Sideromycins are not only synthetic products, as naturally occurring sideromycins are produced, e.g., by Streptomyces species. Covalent conjugates of siderophores with antibiotics are also known as sideromycins they mimic the siderophore–iron complexes to be actively imported by bacteria. ![]() Siderophores are high-affinity iron chelators that are produced and excreted by bacteria and are actively re-imported as siderophore–iron complexes. One of the strategies to overcome this drawback is the exploitation of the bacterial iron-acquisition system, also known as siderophore system. One of the major drawbacks of the previously reported thiol-containing inhibitors is the comparably high lipophilicity, which is considered to be a limiting factor for the transport of the inhibitor through the outer membrane of Gram-negative pathogens into periplasm. The most advanced MBL inhibitor, taniborbactam ( Figure 1), is currently under investigation in clinical phase III trials for the treatment of complicated urinary tract infections. While a number of SBL inhibitors, in combination with ß-lactam antibiotics, are approved for therapy, no inhibitor of MBLs has yet been approved. Serine-β-lactamases (SBLs) use a nucleophilic serine to cleave the β-lactam core, while metallo-β-lactamases (MBLs) enable the nucleophilic attack of an activated water molecule, coordinated by one or two Zn 2+ ions in the active site. β-Lactamases can be separated in accordance to the underlying hydrolysis mechanism. Therefore, the inhibitors of β-lactamases are considered as effective antibiotic adjuvants, which can restore the activity of β-lactam antibiotics. β-Lactamases, which inactivate β-lactam antibiotics, are produced by many multi-resistant Gram-negative bacteria and represent the most effective resistance mechanisms. In the fight against these pathogens, approved anti-infectives are becoming increasingly ineffective. ![]() Multidrug-resistant Gram-negative pathogens are regarded as one of the major threats for human health. Thus, siderophore-containing MBL inhibitors might be a valuable strategy to overcome bacterial MBL-mediated resistance to beta lactam antibiotics. pneumoniae, while leaving HUVEC cells completely unaffected. Finally, we could show that this compound restores the antibiotic activity of imipenem in NDM-1-expressing K. We demonstrated that the most potent catechol-containing MBL inhibitor is able to bind Fe 3+ ions. We synthesised two catechol-containing MBL inhibitors, as well as their dimethoxy counterparts, and tested them for in vitro inhibitory activity against NDM-1, VIM-1, and IMP-7. In this study, we propose the integration of catechol substructures into the design of thiol-based MBL inhibitors, aiming at mimicking bacterial siderophores for the active uptake by the iron acquisition system of bacteria. Metallo beta lactamases (MBLs) are among the most problematic resistance mechanisms of multidrug-resistant Gram-negative pathogens due to their broad substrate spectrum and lack of approved inhibitors.
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