Abstract
The rise of multidrug-resistant (MDR) pathogens causes an increasing challenge to public health. Antimicrobial peptides are considered a possible solution to this problem. HBV core protein (HBc) contains an arginine-rich domain (ARD) at its C-terminus, which consists of 16 arginine residues separated into four clusters (ARD I to IV). In this study, we demonstrated that the peptide containing the full-length ARD I–IV (HBc147-183) has a broad-spectrum antimicrobial activity at micro-molar concentrations, including some MDR and colistin (polymyxin E)-resistant Acinetobacter baumannii. Furthermore, confocal fluorescence microscopy and SYTOX Green uptake assay indicated that this peptide killed Gram-negative and Gram-positive bacteria by membrane permeabilization or DNA binding. In addition, peptide ARD II–IV (HBc153-176) and ARD I–III (HBc147-167) were found to be necessary and sufficient for the activity against P. aeruginosa and K. peumoniae. The antimicrobial activity of HBc ARD peptides can be attenuated by the addition of LPS. HBc ARD peptide was shown to be capable of direct binding to the Lipid A of lipopolysaccharide (LPS) in several in vitro binding assays. Peptide ARD I–IV (HBc147-183) had no detectable cytotoxicity in various tissue culture systems and a mouse animal model. In the mouse model by intraperitoneal (i.p.) inoculation with Staphylococcus aureus, timely treatment by i.p. injection with ARD peptide resulted in 100-fold reduction of bacteria load in blood, liver and spleen, as well as 100% protection of inoculated animals from death. If peptide was injected when bacterial load in the blood reached its peak, the protection rate dropped to 40%. Similar results were observed in K. peumoniae using an IVIS imaging system. The finding of anti-microbial HBc ARD is discussed in the context of commensal gut microbiota, development of intrahepatic anti-viral immunity and establishment of chronic infection with HBV. Our current results suggested that HBc ARD could be a new promising antimicrobial peptide.
Highlights
The increase of drug-resistant pathogens caused by the extensive use of traditional antibiotics is a serious concern worldwide
We found different bactericidal mechanisms of the arginine-rich domain (ARD) peptides, which involved LPS binding, DNA binding and membrane permeabilization in various tested bacteria, such as P. aeruginosa, K. pneumoniae, E. coli and S. aureus
We found that this ARD peptide was effective for colistin-resistant A. baumannii
Summary
The increase of drug-resistant pathogens caused by the extensive use of traditional antibiotics is a serious concern worldwide. Antimicrobial peptides (AMP) are a new class of antibiotics with a new mode of action and remarkable therapeutic effects [1]. They contain 10–50 amino acids, with an overall positive charge and an amphipathic structure. It is well known that most AMPs can directly bind to bacteria membrane and kill them by disrupting membrane or targeting intracellular components [3,4,5]. Most importantly, they are effective to antibiotics-resistant pathogens [6,7]. This unique feature has encouraged the development of AMPs as novel antibiotics in the last few decades
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