Abstract
The emergence of antibiotic-resistant bacteria has threatened our health worldwide. There is an urgent need for novel antibiotics. Previously, we identified a novel 37-mer antimicrobial peptide (AMP), HBcARD, with broad spectrum antimicrobial activity. Here, we improved the efficacy of HBcARD, by re-engineering the peptide, including the addition of a new cysteine to its C-terminus (CTC). The new 28-mer derivative, D-150-177C, contains all D-form arginines, in addition to a C-terminal cycteine. This peptide can kill antibiotic-resistant clinical isolates of Gram-negative bacteria, and is more potent than the parental HBcARD peptide in a mouse sepsis model. In another lung infection mouse model, D-150-177C showed protection efficacy against colistin-resistant Acinetobacter baumannii. Unlike colistin, we observed no acute toxicity of D-150-177C in vivo. Interestingly, we found that CTC modification could enhance the antibacterial activity of several other AMPs, such as buforinII and lysin. The potential application and mechanism of this CTC method as a general approach to improving drug efficacy, warrants further investigation in the future.
Highlights
Antibiotics have been used for the treatment of bacterial infection for more than 60 years
In our previous results (Chen et al, 2013), we found that the antimicrobial activity against S. aureus was diminished, when the HBcARD peptide lost the last 8 amino acids (SQSRESQC)
To further improve the potency of our lead compound HBcARD, we tested the antimicrobial activity of several HBcARD derivatives, including peptides modified by truncation and D-arginine substitution for L-arginine (Figure 1)
Summary
Antibiotics have been used for the treatment of bacterial infection for more than 60 years. There are several life-threatening antibiotics“ESKAPE” pathogens, which caused the majority of nosocomial infection, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (Rice, 2008). This situation was headlined as “Bad bugs, No drugs” by The Infectious Diseases Society of America (Boucher et al, 2009). It is urgent to develop new antibiotics for clinical treatment. New derivatives with improved potency have largely been based on the structure-activity relationship, by using these natural AMPs as a reference
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