Antibacterial efficacy evaluation and mechanism probe of small lysine chalcone peptide mimics.

Bacterial resistance is a growing threat to public health and a significant barrier to anti-infective treatment. Consequently, the development of novel antibacterial strategies to address this issue is critical. Herein, we developed a series of chalcone-alkyl-lysine compounds by mimicking the chemical structure and antibacterial properties of cationic antimicrobial peptides. Most of the compounds showed significant antibacterial activity against Gram-positive and Gram-negative bacteria. Compound 6d displayed potent antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), with MICs of 1-4 µg/mL. In addition, 6d exhibited excellent antibacterial activity against clinical MRSA and NDM-positive isolates, bactericidal properties, low resistance frequency. The mechanism studies revealed that compound 6d destroys bacterial cell membranes by interacting with phosphatidylglycerol (PG), causing the production of reactive oxygen species (ROS) and the leakage of nucleic acids, resulting in bacterial death. Furthermore, compound 6d did not exhibit any observable toxicity in HeLa and HEK293 cells at 8 × MIC. As a result, the findings suggest that compound 6d has potential therapeutic effects against bacterial infections and could be a promising drug candidate for future research.

Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi Metallo-ß-lactamase-1.

New Delhi Metallo-ß-lactamase-1 (NDM-1), a Zn (II)-dependent enzyme, can catalyze the hydrolysis of almost all ß-lactam antibiotics including carbapenems, resulting in bacterial antibiotic resistance, which threatens public health globally. Based on our finding that H2dedpa is as an efficient NDM-1 inhibitor, a series of H2dedpa derivatives was systematically prepared. These compounds exhibited significant activity against NDM-1, with IC50 values 0.06-0.94 µM. In vitro, compounds 6k and 6n could restore the activity of meropenem against Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis possessing either NDM or IMP. In particular, the activity of meropenem against E. coli producing NDM-4 could be improved up to 5333 times when these two compounds were used. Time-kill cell-based assays showed that 99.9% of P. mirabilis were killed when treated with meropenem in combination with compound 6k or 6n. Furthermore, compounds 6k and 6n were nonhemolytic (HC50 > 1280 µg/mL) and showed low toxicity toward mammalian (HeLa) cells. Mechanistic studies indicated that compounds 6k and 6n inhibit NDM-1 by chelating the Zn2+ ion of the enzyme.