Novel antimicrobial peptide CPF‐C1 analogs with superior stabilities and activities against multidrug‐resistant bacteria

Abstract

As numerous clinical isolates are resistant to most conventional antibiotics, infections caused by multidrug-resistant bacteria are associated with a higher death rate. Antimicrobial peptides show great potential as new antibiotics. However, a major obstacle to the development of these peptides as useful drugs is their low stability. To overcome the problem of the natural antimicrobial peptide CPF-C1, we designed and synthesized a series of analogs. Our results indicated that by introducing lysine, which could increase the number of positive charges, and by introducing tryptophan, which could increase the hydrophobicity, we could improve the antimicrobial activity of the peptides against multidrug-resistant strains. The introduction of d-amino acids significantly improved stability. Certain analogs demonstrated antibiofilm activities. In mechanistic studies, the analogs eradicated bacteria not just by interrupting the bacterial membranes, but also by linking to DNA, which was not impacted by known mechanisms of resistance. In a mouse model, certain analogs were able to significantly reduce the bacterial load. Among the analogs, CPF-9 was notable due to its greater antimicrobial potency in vitro and in vivo and its superior stability, lower hemolytic activity, and higher antibiofilm activity. This analog is a potential antibiotic candidate for treating infections induced by multidrug-resistant bacteria.

Design and characterization of chionodracine-derived antimicrobial peptides with enhanced activity against drug-resistant human pathogens

“…1,2 AMPs represent the rst line of the innate immune system defense against pathogens and usually show a broad spectrum of action against fungi, bacteria, and protozoans. AMPs can interact with and insert into the anionic cell membranes of microorganisms [3][4][5] usually performing their functions via cell membrane disruption. 6 An important class of AMPs is composed by short peptides (less than 50 amino acids) that fold into stable amphipathic a-helical structures in the presence of membranes, [7][8][9][10][11][12] although other conformations, such as b-peptides or more complex folds, are also found in nature.…”

Antibacterial activities and molecular mechanism of amino‐terminal fragments from pig nematode antimicrobial peptide CP‐1

“…To test stability to enzyme, the peptides were incubated in the presence of different concentrations of trypsin (62.5, 125, 250, and 500 μg/ml) at 37°C for 1 hr. After the treatment, the reaction was terminated by heat treatment at 60°C for 10 min . For testing antimicrobial activity in the presence of serum, human serum was dissolved in the MHB to reach the final concentrations of 25% and 50%.…”

“…The food and water were supplied ad libitum; animals were acclimatized for 2–3 days prior to the initiation of the study. The in vivo antimicrobial activity of WL3 was determined by colony counting of blood and various organs . E. coli ATCC 25922 was adopted as pathogenic bacteria for infection model in this study.…”

Design of a new pH‐activatable cell‐penetrating peptide for drug delivery into tumor cells

“…Measurements were performed in a 1 mm path length under nitrogen flush at room temperature with 50‐nm/min scanning speed, 0.1‐nm step size, 0.5‐s response time, and 1 nm bandwidth. The spectrum (190–260 nm) was recorded, and the α‐helical content of peptide was evaluated according to the previous method (Xie et al., ).…”