Development of Aromatic-Linked Diamino Acid Antimicrobial Peptide Mimics with Low Hemolytic Toxicity and Excellent Activity against Methicillin-Resistant Staphylococcus aureus (MRSA).

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have become one of the biggest threats to public health. To develop new antibacterial agents against MRSA, a series of diamino acid compounds with aromatic nuclei linkers were designed and synthesized. Compound 8j, which exhibited low hemolytic toxicity and the best selectivity against S. aureus (SI > 2000), showed good activity against clinical MRSA isolates (MIC = 0.5-2 µg/mL). Compound 8j was able to quickly kill bacteria without inducing bacterial resistance. A mechanistic study and transcriptome analysis revealed that compound 8j can act on phosphatidylglycerol and induce the accumulation of endogenous reactive oxygen species, which can destroy bacterial membranes. Importantly, compound 8j achieved a 2.75 log reduction of MRSA count at 10 mg/kg/d in a mouse subcutaneous infection model. These findings suggested that compound 8j had the potential to be an antibacterial agent against MRSA.

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.

Prediction of the effect of fine grit on the MLVSS/MLSS ratio of activated sludge.

This paper investigated the suspension properties of fine grit with different particle sizes in a bioreactor and developed a model to predict its effect on the ratio of mixed liquor volatile suspended solids to the mixed liquor suspended solids (MLVSS/MLSS) of activated sludge. The experimental results revealed that a smaller particle size corresponds to a larger suspension ratio, defined as the proportion of fine grit brought in by influent that is suspended in the activated sludge, and a smaller MLVSS/MLSS ratio. The model demonstrated that the effect of fine grit on the MLVSS/MLSS ratio is related to the fine grit concentration and chemical oxygen demand in influent and the observed sludge yield. However, fine grit has no influence on the activity of microorganisms. Wastewater treatment plants (WWTPs) can adjust MLSS based on the MLVSS/MLSS ratio to ensure the stability of MLVSS, which can achieve the stable operation of WWTPs.