Membrane-active amino acid-coupled polyetheramine derivatives with high selectivity and broad-spectrum antibacterial activity

Abstract

Membrane active antimicrobial peptide mimics have been considered as promising alternatives to antibiotics, which interact with bacterial cell membranes to combat bacteria and avoid the emergence of multidrug-resistant bacteria. Herein, a series of star-shaped and membrane-active cationic polyetheramides derived from amino acids, were synthesized via condensation of amino acids and polyetheamine (T403). The antibacterial and anti-biofilm activitives as well as the biocompatibility of these amino acids derived polyetheramides (AAPEAs) were investigated in detail. The star-shaped AAPEAs showed high-efficient and broad-spectrum antibacterial activity against the Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) pathogens. In addition, the antibacterial activity was significantly affected by the type of amino acid. L-Trp-T403, which was obtained from L-tryptophan and polyetheramine, exhibited the best antibacterial activity with the minimum inhibitory concentration (MIC) of 1 µg/mL against methicillin-resistant S. aureus (MRSA). Time-kill kinetics and multi-passage resistance tests experiments indicated that L-Trp-T403 could rapidly kill bacteria within 1 h. This compound also showed potent antibacterial activity against bacteria over many passages. Moreover, the AAPEAs exhibited outstanding stability and long-term antibacterial activity in complex mammalian body fluids, as well as good biocompatibility, low hemolytic activity, slight toxicity for mammalian cell (L929) and low in vivo toxicity. The antibacterial activity of L-Trp-T403 was found to be based on the disruption of bacterial membranes, which leads to the leakage of the internal cytoplasm. The AAPEAs possessed high antibacterial and anti-biofilm activity, thus, they are promising to be used as long-term and biofilm-disrupting antimicrobial agents. STATEMENT OF SIGNIFICANCE: The growing epidemic of MDR-bacteria is becoming a severe public health threat. Here, a series of amino acids derived polyetheramides (AAPEAs) with a star-shaped polyether amide scaffold was synthesized. The star-shaped AAPEAs displayed broad-spectrum antibacterial activity against Gram-positive, Gram-negative bacteria and drug-resistant bacteria MRSA. Notably, the star-shaped AAPEAs were stable under plasma conditions and showed outstanding stability and long-term antibacterial activity in various complex mammalian fluids. Moreover, these star-shaped AAPEAs not only inhibited the formation of biofilms but also disrupted the established biofilms. Furthermore, the membrane-active AAPEAs eradicated bacteria via the fast membrane lytic mechanism, thus plausibly overcoming the MDR effect. These results demonstrate that membrane-active AAPEAs can serve as emerging long-term and biofilm-disrupting antimicrobial agents to treat biofilm-related infections.

Keywords: Amino acids; Antibacterial; Low cytotoxicity; Polyetheramine.