Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors

Abstract

Antimicrobial resistance (AMR), and in particular antibacterial resistance, is an increasingly serious threat to global public health. AMR develops when a microorganism (bacteria, fungus, virus or parasites) no longer responds to a drug to which it was originally sensitive. [1][2] Antibiotics have an enormous impact on modern medicine. They are essential in the treatment of many human diseases such as urinary tract infections, wound infections, bloodstream infections, pneumonia, tuberculosis and they are a prerequisite for chemotherapy or surgery. Without harmonized and immediate worldwide action to develop agents countering highly resistant bacteria (e.g. Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus), the world is heading towards a post-antibiotic era in which common infections could once again become life threatening. [1][2] The increase in mortality with bloodstream infections caused by methicillin-resistant S. aureus (MRSA) and third-generation cephalosporin-resistant E. coli is significant, and the prolongation of hospital stay imposes a considerable burden on health care systems. [3][4] The introduction of more potent alternatives of existing antibiotics provides only temporary

ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

“…TPA is a known lipophilic zinc chelator with high affinity (10 11 M) towards Zn 2+ and has previously been shown to inhibit MBLs (23)(24)(25)(26). Synthesis of ZN148 is achieved through a high-on September 1, 2020 by guest http://aac.asm.org/ Downloaded from yield, 3-step synthesis from commercially available building blocks (Fig.…”

Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors

“…We included the previously reported compound 15 here for completeness. 23 Note that methyl esters have been preserved in 8-14, as the corresponding free acids have performed poorly in biological assays (results not shown). All products 8-20 show an attachment of chelator moiety either at point C or point E (Fig.…”

“…The DPA amine 5 was prepared from N-Boc-protected 4-(2-aminoethyl)aniline as previously described. 23 Quantitative conversion to the acid 1 was achieved by reaction with succinic anhydride. For the dipicolyl 1,2,3-triazolylmethylamine chelators (DPTA), the amine 6 was obtained by copperIJI)-mediated azide-alkyne cycloaddition (CuAAC) between tert-butyl 4-azidophenethylcarbamate (21), 24 and N-propargyl-diIJ2-picolyl)amine (22), 25 followed by deprotection with HCl.…”

“…We have previously reported results on how variations in the linker between peptide fragment and zinc chelator influenced meropenem MIC restoration and eukaryotic toxicity. 13,23 In this present paper, we have explored how variations in the peptide, the corresponding attachment point, as well as differences in chelator strength, influenced the effect on meropenem MIC and toxicity of these compounds. As shown in Tables 1 and 2, data suggest a strong dependence upon the strength of the chelator for reducing the MIC of meropenem.…”

“…20,21 As it would later turn out, current evidence suggests this reasoning to be too simplistic and such dual activity cannot be expected, 22 but we have included such compounds in this study for completeness. In a recent report, we studied the linkers between the chelators and the peptides, 23 but found that the biological effect was mostly due to the strength of the zinc chelator. We, therefore, have not performed a comprehensive investigation of all possible chelator-linkerpeptide combinations for the chelators and peptides in the present work.…”