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Short Symmetric-End Antimicrobial Peptides Centered on ?-Turn Amino Acids Unit Improve Selectivity and Stability.

ABSTRACT: Antimicrobial peptides (AMPs) are excellent candidates to combat the increasing number of multi- or pan-resistant pathogens worldwide based on their mechanism of action, which is different from that of antibiotics. In this study, we designed short peptides by fusing an ?-helix and ?-turn sequence-motif in a symmetric-end template to promote the higher cell selectivity, antibacterial activity and salt-resistance of these structures. The results showed that the designed peptides PQ and PP tended to form an ?-helical structure upon interacting with a membrane-mimicking environment. They displayed high cell selectivity toward bacterial cells over eukaryotic cells. Their activities were mostly maintained in the presence of different conditions (salts, serum, heat, and pH), which indicated their stability in vivo. Fluorescence spectroscopy and electron microscopy analyses indicated that PP and PQ killed bacterial cells through membrane pore formation, thereby damaging membrane integrity. This study revealed the potential application of these designed peptides as new candidate antimicrobial agents.

SUBMITTER: Dong N

PROVIDER: S-EPMC6277555 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Short Symmetric-End Antimicrobial Peptides Centered on β-Turn Amino Acids Unit Improve Selectivity and Stability.

Dong Na N Chou Shuli S Li Jiawei J Xue Chenyu C Li Xinran X Cheng Baojing B Shan Anshan A Xu Li L

Frontiers in microbiology 20181127

Antimicrobial peptides (AMPs) are excellent candidates to combat the increasing number of multi- or pan-resistant pathogens worldwide based on their mechanism of action, which is different from that of antibiotics. In this study, we designed short peptides by fusing an α-helix and β-turn sequence-motif in a symmetric-end template to promote the higher cell selectivity, antibacterial activity and salt-resistance of these structures. The results showed that the designed peptides PQ and PP tended t ...[more]

PMID: 30538681

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Project description:BackgroundAntimicrobial peptides (AMPs) are receiving increasing attention due to resistance development against conventional antibiotics. Pseudomonas aeruginosa and Staphylococcus aureus are two major pathogens involved in an array of infections such as ocular infections, cystic fibrosis, wound and post-surgery infections, and sepsis. The goal of the study was to design novel AMPs against these pathogens.Methodology and principal findingsAntibacterial activity was determined by radial diffusion, viable count, and minimal inhibitory concentration assays, while toxicity was evaluated by hemolysis and effects on human epithelial cells. Liposome and fluorescence studies provided mechanistic information. Protease sensitivity was evaluated after subjection to human leukocyte elastase, staphylococcal aureolysin and V8 proteinase, as well as P. aeruginosa elastase. Highly active peptides were evaluated in ex vivo skin infection models. C-terminal end-tagging by W and F amino acid residues increased antimicrobial potency of the peptide sequences GRRPRPRPRP and RRPRPRPRP, derived from proline arginine-rich and leucine-rich repeat protein (PRELP). The optimized peptides were antimicrobial against a range of gram-positive S. aureus and gram-negative P. aeruginosa clinical isolates, also in the presence of human plasma and blood. Simultaneously, they showed low toxicity against mammalian cells. Particularly W-tagged peptides displayed stability against P. aeruginosa elastase, and S. aureus V8 proteinase and aureolysin, and the peptide RRPRPRPRPWWWW-NH(2) was effective against various "superbugs" including vancomycin-resistant enterococci, multi-drug resistant P. aeruginosa, and methicillin-resistant S. aureus, as well as demonstrated efficiency in an ex vivo skin wound model of S. aureus and P. aeruginosa infection.Conclusions/significanceHydrophobic C-terminal end-tagging of the cationic sequence RRPRPRPRP generates highly selective AMPs with potent activity against multiresistant bacteria and efficiency in ex vivo wound infection models. A precise "tuning" of toxicity and proteolytic stability may be achieved by changing tag-length and adding W- or F-amino acid tags.

Project description:Diarrhea is one of the most common infirmities affecting international travelers, occurring in 20 to 50% of persons from industrialized countries visiting developing regions. Enterotoxigenic Escherichia coli (ETEC) is the most common causative agent and is isolated from approximately half of the cases of traveler's diarrhea. Rifaximin, a largely water-insoluble, nonabsorbable (<0.4%) antibiotic that inhibits bacterial RNA synthesis, is approved for use for the treatment of traveler's diarrhea caused by diarrheagenic E. coli. However, the drug has minimal effect on the bacterial flora or the infecting E. coli strain in the aqueous environment of the colon. The purpose of the present study was to evaluate the antimicrobial effect and bioavailability of rifaximin in aqueous solution in the presence and absence of physiologic concentrations of bile acids. The methods used included growth measurement of ETEC (strain H10407), rifaximin solubility measurements, total bacterial protein determination, and assessment of the functional activity of rifaximin by monitoring inhibition of bacterial beta-galactosidase expression. Solubility studies showed rifaximin to be 70- to 120-fold more soluble in bile acids (approximately 30% in 4 mM bile acids) than in aqueous solution. Addition of both purified bile acids and human bile to rifaximin at subinhibitory and inhibitory concentrations significantly improved the drug's anti-ETEC effect by 71% and 73%, respectively, after 4 h. This observation was confirmed by showing a decrease in the overall amount of total bacterial protein expressed during incubation of rifaximin plus bile acids. Rifaximin-treated samples containing bile acids inhibited the expression of ETEC beta-galactosidase at a higher magnitude than samples that did not contain bile acids. The study provides data showing that bile acids solubilize rifaximin on a dose-response basis, increasing the drug's bioavailability and antimicrobial effect. These observations suggest that rifaximin may be more effective in the treatment of infections in the small intestine, due to the higher concentration of bile in this region of the gastrointestinal tract than in the colon. The water insolubility of rifaximin is the likely explanation for the drug's minimal effects on colonic flora and fecal pathogens, despite in vitro susceptibility.

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Short Symmetric-End Antimicrobial Peptides Centered on ?-Turn Amino Acids Unit Improve Selectivity and Stability.

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Short Symmetric-End Antimicrobial Peptides Centered on β-Turn Amino Acids Unit Improve Selectivity and Stability.

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