Peptide-mimicking poly(2-oxazoline)s as adjuvants to enhance activities and antibacterial spectrum of polymyxin B

Antibiotic-resistant ESKAPE bacteria have become a significant threat to human health due to the ineffectiveness of clinically used broad-spectrum antibiotics. Combination therapy of antibiotic and adjuvant has emerged as a promising strategy to overcome antibiotic-resistant bacteria. However, the antibiotic-adjuvant combination with potent and broad-spectrum antimicrobial activities against all ESKAPE bacteria remains a huge challenge. Herein, we proposed an effective combination strategy of using polymyxin B (PMB) as the antibiotic, which exhibited potent activity against Gram-negative ESKAPE bacteria, and host defense peptide (HDP)-mimicking cationic antimicrobial poly(2-oxazoline)s that target bacterial membrane as the adjuvant. A series of cationic poly(2-oxazoline)s with varying hydrophobic side chain lengths were synthesized via the controllable 2-oxazoline polymerization. The results indicate that the combination effect of PMB and HDP-mimicking poly(2-oxazoline)s exhibits the gradual change from antagonistic effect to synergistic effect as the hydrophobicity and ability to disrupt bacterial membrane of poly(2-oxazoline)s increase. Moreover, the optimal poly(2-oxazoline) EACA-POX 20 significantly enhances the antibacterial activity of PMB, especially against Gram-positive ESKAPE bacteria with 16–32 folds enhancement. The combination strategy of EACA-POX 20 and PMB effectively broadens the antibacterial spectrum of PMB, enabling it to combat all drug-resistant ESKAPE bacteria. This study presents a promising approach for combating ESKAPE bacteria.