Beta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria
Abstract Background Avian β-defensins (AvBD) are cationic antimicrobial peptides (CAMP) with broad-spectrum antimicrobial activity, chemotactic property, and low host cytotoxicity. However, their bactericidal activity is greatly compromised under physiological salt concentrations which limits the us...
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| Format: | Article |
| Language: | English |
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BMC
2018-06-01
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| Series: | BMC Microbiology |
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| Online Access: | http://link.springer.com/article/10.1186/s12866-018-1190-z |
| _version_ | 1819148551534411776 |
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| author | Ming Yang Chunye Zhang Michael Z. Zhang Shuping Zhang |
| author_facet | Ming Yang Chunye Zhang Michael Z. Zhang Shuping Zhang |
| author_sort | Ming Yang |
| collection | DOAJ |
| description | Abstract Background Avian β-defensins (AvBD) are cationic antimicrobial peptides (CAMP) with broad-spectrum antimicrobial activity, chemotactic property, and low host cytotoxicity. However, their bactericidal activity is greatly compromised under physiological salt concentrations which limits the use of these peptides as therapeutic agents. The length and the complex structure involving three conserved disulfide bridges are additional drawbacks associated with high production cost. In the present study, short linear CAMPs (11 to 25 a.a. residues) were developed based on the key functional components of AvBDs with additional modifications. Their biological functions were characterized. Results CAMP-t1 contained the CCR2 binding domain (N-terminal loop and adjacent α-helix) of AvBD-12 whereas CAMP-t2 comprised the key a.a. residues responsible for the concentrated positive surface charge and hydrophobicity of AvBD-6. Both CAMP-t1 and CAMP-t2 demonstrated strong antimicrobial activity against Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus pseudintermedius. However, CAMP-t1 failed to show chemotactic activity and CAMP-t2, although superior in killing Staphylococcus spp., remained sensitive to salts. Using an integrated design approach, CAMP-t2 was further modified to yield CAMP-A and CAMP-B which possessed the following characteristics: α-helical structure with positively and negatively charged residues aligned on the opposite side of the helix, lack of protease cutting sites, C-terminal poly-Trp tail, N-terminal acetylation, and C-terminal amidation. Both CAMP-A and CAMP-B demonstrated strong antimicrobial activity against multidrug-resistant P. aeruginosa and methicillin-resistant S. pseudintermedius (MRSP) strains. These peptides were resistant to major proteases and fully active at physiological concentrations of NaCl and CaCl2. The peptides were minimally cytotoxic to avian and murine cells and their therapeutic index was moderate (≥ 4.5). Conclusions An integrated design approach can be used to develop short and potent antimicrobial peptides, such as CAMP-A and CAMP-B. The advantageous characteristics, including structural simplicity, resistance to salts and proteases, potent antimicrobial activity, rapid membrane attacking mode, and moderate therapeutic index, suggest that CAMP-A and CAMP-B are excellent candidates for development as therapeutic agents against multidrug-resistant P. aeruginosa and methicillin-resistant staphylococci. |
| first_indexed | 2024-12-22T13:47:31Z |
| format | Article |
| id | doaj.art-8a885fed8c1b46a3b5832ffad06bd9cc |
| institution | Directory Open Access Journal |
| issn | 1471-2180 |
| language | English |
| last_indexed | 2024-12-22T13:47:31Z |
| publishDate | 2018-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Microbiology |
| spelling | doaj.art-8a885fed8c1b46a3b5832ffad06bd9cc2022-12-21T18:23:45ZengBMCBMC Microbiology1471-21802018-06-0118111410.1186/s12866-018-1190-zBeta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteriaMing Yang0Chunye Zhang1Michael Z. Zhang2Shuping Zhang3Department of Veterinary Pathobiology, College of Veterinary Medicine, University of MissouriDepartment of Veterinary Pathobiology, College of Veterinary Medicine, University of MissouriDepartment of Biomedical Science, College of Veterinary Medicine, University of MissouriDepartment of Veterinary Pathobiology, College of Veterinary Medicine, University of MissouriAbstract Background Avian β-defensins (AvBD) are cationic antimicrobial peptides (CAMP) with broad-spectrum antimicrobial activity, chemotactic property, and low host cytotoxicity. However, their bactericidal activity is greatly compromised under physiological salt concentrations which limits the use of these peptides as therapeutic agents. The length and the complex structure involving three conserved disulfide bridges are additional drawbacks associated with high production cost. In the present study, short linear CAMPs (11 to 25 a.a. residues) were developed based on the key functional components of AvBDs with additional modifications. Their biological functions were characterized. Results CAMP-t1 contained the CCR2 binding domain (N-terminal loop and adjacent α-helix) of AvBD-12 whereas CAMP-t2 comprised the key a.a. residues responsible for the concentrated positive surface charge and hydrophobicity of AvBD-6. Both CAMP-t1 and CAMP-t2 demonstrated strong antimicrobial activity against Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus pseudintermedius. However, CAMP-t1 failed to show chemotactic activity and CAMP-t2, although superior in killing Staphylococcus spp., remained sensitive to salts. Using an integrated design approach, CAMP-t2 was further modified to yield CAMP-A and CAMP-B which possessed the following characteristics: α-helical structure with positively and negatively charged residues aligned on the opposite side of the helix, lack of protease cutting sites, C-terminal poly-Trp tail, N-terminal acetylation, and C-terminal amidation. Both CAMP-A and CAMP-B demonstrated strong antimicrobial activity against multidrug-resistant P. aeruginosa and methicillin-resistant S. pseudintermedius (MRSP) strains. These peptides were resistant to major proteases and fully active at physiological concentrations of NaCl and CaCl2. The peptides were minimally cytotoxic to avian and murine cells and their therapeutic index was moderate (≥ 4.5). Conclusions An integrated design approach can be used to develop short and potent antimicrobial peptides, such as CAMP-A and CAMP-B. The advantageous characteristics, including structural simplicity, resistance to salts and proteases, potent antimicrobial activity, rapid membrane attacking mode, and moderate therapeutic index, suggest that CAMP-A and CAMP-B are excellent candidates for development as therapeutic agents against multidrug-resistant P. aeruginosa and methicillin-resistant staphylococci.http://link.springer.com/article/10.1186/s12866-018-1190-zCationic antimicrobial peptidesPeptide designSalt resistanceAntimicrobial activityMultidrug-resistant Pseudomonas aeruginosaMethicillin-resistant Staphylococcus pseudintermedius |
| spellingShingle | Ming Yang Chunye Zhang Michael Z. Zhang Shuping Zhang Beta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria BMC Microbiology Cationic antimicrobial peptides Peptide design Salt resistance Antimicrobial activity Multidrug-resistant Pseudomonas aeruginosa Methicillin-resistant Staphylococcus pseudintermedius |
| title | Beta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria |
| title_full | Beta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria |
| title_fullStr | Beta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria |
| title_full_unstemmed | Beta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria |
| title_short | Beta-defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria |
| title_sort | beta defensin derived cationic antimicrobial peptides with potent killing activity against gram negative and gram positive bacteria |
| topic | Cationic antimicrobial peptides Peptide design Salt resistance Antimicrobial activity Multidrug-resistant Pseudomonas aeruginosa Methicillin-resistant Staphylococcus pseudintermedius |
| url | http://link.springer.com/article/10.1186/s12866-018-1190-z |
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