Abstract
The increase in the prevalence of multidrug-resistant Acinetobacter baumannii (MDRAB) strains is a serious public health concern. Antimicrobial peptides (AMPs) are a possible solution to this problem. In this study, we examined whether AMPs could be derived from phage endolysins. We synthesized four AMPs based on an amphipathic helical region in the C-terminus of endolysin LysAB2 encoded by the A. baumannii phage ΦAB2. These peptides showed potent antibacterial activity against A. baumannii (minimum inhibitory concentration, 4–64 μM), including some MDR and colistin-resistant A. baumannii. Of the four peptides, LysAB2 P3, with modifications that increased its net positive charge and decreased its hydrophobicity, showed high antibacterial activity against A. baumannii but little haemolytic and no cytotoxic activity against normal eukaryotic cells. The results of electron microscopy experiments and a fluorescein isothiocyanate staining assay indicated that this peptide killed A. baumannii through membrane permeabilization. Moreover, in a mouse intraperitoneal infection model, at 4 h after the bacterial injection, LysAB2 P3 decreased the bacterial load by 13-fold in ascites and 27-fold in blood. Additionally, LysAB2 P3 rescued sixty percent of mice heavily infected with A. baumannii from lethal bacteremia. Our results confirmed that bacteriophage endolysins are a promising resource for developing effective AMPs.
Highlights
The emergence of multidrug-resistant Acinetobacter baumannii (MDRAB) strains is a serious public health concern[1, 2]
The minimum inhibition concentration (MIC) of LysAB2 P1 and P3 for standard A. baumannii strains were in the range of 4–8 μM, approximately 8–16 times lower than the MIC of LysAB2 P0
Since in vivo plasma protein binding may modulate the effective binding of Antimicrobial peptides (AMPs) to their targets, we examined the bactericidal activities of LysAB2 P3 in human blood plasma
Summary
The emergence of multidrug-resistant Acinetobacter baumannii (MDRAB) strains is a serious public health concern[1, 2]. Some endolysins, especially those obtained from phages infecting gram-negative bacteria, can affect bacteria through mechanisms that are completely independent of their enzymatic activity[11,12,13] In some of these cases, it was found that amphipathic peptides containing basic amino acids interact with negatively charged membrane elements such as LPS in gram-negative bacteria[9, 11]. Thandar et al recently showed that the C-terminal region of an Acinetobacter phage lysin displayed more lethal activity against Acinetobacter than the intact lysin molecule[17] These clues suggest that A. baumannii phage endolysins may be a promising source of potent AMPs. In the present study, we designed and synthesized four AMPs based on the sequence of aa 113–145 of LysAB2 and named these peptides LysAB2 P0-P3. The effectiveness of the antibacterial activity of LysAB2 P3 in a mouse intraperitoneal infection model was evaluated
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