Abstract
Antimicrobial peptides (AMPs) have been developed for the treatment of bacterial infections, but their applications are limited to topical infections since they are sequestered and inhibited in serum. Here we have discovered that the inhibition of AMPs by human serum was mediated through high-density lipoproteins (HDL) which are known to remove cholesterol from peripheral tissues. The susceptibility of AMPs to HDL varied depending on the degree of hydrophobicity of AMPs and their binding affinities to HDL. The phospholipids, such as phosphatidylcholine, of HDL were essential for AMP-binding. The dynamic binding interactions between AMPs and HDL were mediated through the hydrophobic interactions rather than by ionic strength. Interestingly, some AMPs, such as SMAP29, dissociated from the AMP-HDL complex and translocated to bacteria upon contact, while some AMPs, such as LL37, remained in complex with HDL. These results suggest that HDL binds AMPs and facilitates the translocation of them to the bacteria.
Highlights
The widespread use of antibiotics in both medicine and agriculture has contributed to the emergence of drugresistant bacteria 1,2
The antimicrobial activities of Antimicrobial peptides (AMPs), such as LL37 from human, TP4 from fish tilapia, SAAP159 derived from LL37 and synthetic peptide H1α against E. coli were markedly repressed in the presence of 5% human serum (v/v) in comparison with those measured in phosphate buffered saline (PBS) (Fig. 1a top panels)
These serum-mediated repressions of AMPs’ activities were only occasionally observed with SMAP29 from sheep and not at all observed with NRC12 from American plaice, Pleurocidin from Pleuronectes amertcanus or with the peptide-containing antibiotic, Polymyxin B (Fig. 1a bottom panel). To investigate whether these repressions are mediated through the binding of serum components, the mobility-shift of each AMP was analyzed by horizontal native polyacrylamide gel electrophoreses (PAGE)
Summary
The widespread use of antibiotics in both medicine and agriculture has contributed to the emergence of drugresistant bacteria 1,2. Several AMPs are currently under examination in phase II/III clinical trials for their effectiveness in preventing and/or treating microbial infections, such as Omiganan (Migenix), Pexigana acetate (MacroChem) and Iseganan (Ardea Biosciences)[5,6,7] Their applications are limited primarily to topical infections because in circulation they are inhibited by serum proteins. Albumin is the most abundant protein (45 mg/ml), followed by α1-antitrypsin, transferrin, α2-macroglobulin, apolipoprotein B (Apo-B, major component of low density lipoproteins (LDL)), α1-acid glycoprotein and apolipoprotein A-I (Apo-AI, major component of high density lipoproteins (HDL))[8]. They are involved in the transportation of fatty acids, cholesterols, toxins and drugs in the blood. We found that some apparently weaker-bound AMPs translocated from the AMP-HDL complex to bacteria upon contacting the bacteria
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