New derivatives of dipicolinic acid as metallo-β-lactamase NDM-1 inhibitors

Abstract

Resistance to β-lactam antibiotics caused by β-lactamases such as New-Delhi lactamase (NDM-1) has become one of the major challenges in the current antimicrobial therapy. Pyridine-2,6-dicarboxylic acid (DPA) derivatives have been demonstrated to inhibit NDM-1 in a due to the interactions with Zn ion and amino acid residues of the enzyme’s active site. In this study, a series of new 4-substituted DPA derivatives was synthesized. The SAR study has proven that the presence of a substituent at the 4-position of pyridine-2,6-dicarboxylic acid had a certain impact on the NDM-1 inhibitory. Some representatives, e.g., 4e exhibited IC₅₀ values against NDM-1 close to the previously reported hit-compound 4-(3-aminophenyl)pyridine-2,6-dicarboxylic acid. The microdilution broth test confirmed an ability of derivative 4e to increase susceptibility of NDM-1-producing E. coli strain and did not demonstrate cytotoxicity to eukaryotic cells. However, NDM-1 inhibition by 4-substituted derivatives dramatically dropped when Zn²⁺ was added. We observed a strong complexation of 4-modified derivatives with Zn²⁺ similar to unsubstituted pyridine-2,6-dicarboxylic acid. Taken together, a complexation mode of NDM-1 inhibition leading to potential off-target action on other metalloenzymes and low efficiency of structure optimization make DPA derivatives an unproductive scaffold for future development of clinically relevant metallo-β-lactamase inhibitors.