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Anti-Staphylococcal Biofilm Effects of Human Cathelicidin Peptides.

ABSTRACT: Staphylococcus aureus can live together in the form of biofilms to avoid elimination by the host. Thus, a useful strategy to counteract bacterial biofilms is to re-engineer human antimicrobial peptide LL-37 so that it can be used as a remedy for preventing and removing biofilms. This study reports antibiofilm effects of four human cathelicidin LL-37 peptides against community-associated and hospital isolated methicillin-resistant Staphylococcus aureus (MRSA) strains. Although the intact molecule LL-37 inhibited biofilm formation at low concentrations, it did not inhibit bacterial attachment nor disrupt preformed biofilms. However, two 17-residue peptides, GF-17 and 17BIPHE2, inhibited bacterial attachment, biofilm growth, and disrupted established biofilms. An inactive peptide RI-10 was used as a negative control. Our results obtained using the S. aureus mutants in a static biofilm model are consistent with the literature obtained in a flow cell biofilm model. Because 17BIPHE2 is the most effective biofilm disruptor with desired stability to proteases, it is a promising lead for developing new anti-MRSA biofilm agents.

SUBMITTER: Mishra B

PROVIDER: S-EPMC4716589 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Anti-Staphylococcal Biofilm Effects of Human Cathelicidin Peptides.

Mishra Biswajit B Golla Radha M RM Lau Kyle K Lushnikova Tamara T Wang Guangshun G

ACS medicinal chemistry letters 20151204 1

Staphylococcus aureus can live together in the form of biofilms to avoid elimination by the host. Thus, a useful strategy to counteract bacterial biofilms is to re-engineer human antimicrobial peptide LL-37 so that it can be used as a remedy for preventing and removing biofilms. This study reports antibiofilm effects of four human cathelicidin LL-37 peptides against community-associated and hospital isolated methicillin-resistant Staphylococcus aureus (MRSA) strains. Although the intact molecule ...[more]

PMID: 26819677

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Project description:Short antimicrobial peptides are essential to keep us healthy and their lasting potency can inspire the design of new types of antibiotics. This study reports the design of a family of eight-residue tryptophan-rich peptides (TetraF2W) obtained by converting the four phenylalanines in temporin-SHf to tryptophans. The temporin-SHf template was identified from the antimicrobial peptide database (http://aps.unmc.edu/AP). Remarkably, the double arginine variant (TetraF2W-RR) was more effective in killing methicillin-resistant Staphylococcus aureus (MRSA) USA300, but less cytotoxic to human skin HaCat and kidney HEK293 cells, than the lysine-containing dibasic combinations (KR, RK and KK). Killing kinetics and fluorescence spectroscopy suggest membrane targeting of TetraF2W-RR, making it more difficult for bacteria to develop resistance. Because established biofilms on medical devices are difficult to remove, we chose to covalently immobilize TetraF2W-RR onto the polyethylene terephthalate (PET) surface to prevent biofilm formation. The successful surface coating of the peptide is supported by FT-IR and XPS spectroscopies, chemical quantification, and antibacterial assays. This peptide-coated surface indeed prevented S. aureus biofilm formation with no cytotoxicity to human cells. In conclusion, TetraF2W-RR is a short Trp-rich peptide with demonstrated antimicrobial and anti-biofilm potency against MRSA in both the free and immobilized forms. Because these short peptides can be synthesized cost effectively, they may be developed into new antimicrobial agents or used as surface coating compounds.Statement of significanceIt is stunning that the total deaths due to methicillin-resistant Staphylococcus aureus (MRSA) infection are comparable to AIDS/HIV-1, making it urgent to explore new possibilities. This study deals with this problem by two strategies. First, we have designed a family of novel antimicrobial peptides with merely eight amino acids, making it cost effective for chemical synthesis. These peptides are potent against MRSA USA300. Our study uncovers that the high potency of the tryptophan-rich short peptide is coupled with arginines, whereas these Trp- and Arg-rich peptides are less toxic to select human cells than the lysine-containing analogs. Such a combination generates a more selective peptide. As a second strategy, we also demonstrate successful covalent immobilization of this short peptide to the polyethylene terephthalate (PET) surface by first using a chitosan linker, which is easy to obtain. Because biofilms on medical devices are difficult to remove by traditional antibiotics, we also show that the peptide coated surface can prevent biofilm formation. Although rarely demonstrated, we provide evidence that both the free and immobilized peptides target bacterial membranes, rendering it difficult for bacteria to develop resistance. Collectively, the significance of our study is the design of novel antimicrobial peptides provides a useful template for developing novel antimicrobials against MRSA. In addition, orientation-specific immobilization of the same short peptide can prevent biofilm formation on the PET surface, which is widely used in making prosthetic heart valves cuffs and other bio devices.

Project description:Host defense antimicrobial peptides are key components of human innate immunity that plays an indispensible role in human health. While there are multiple copies of cathelicidin genes in horses, cattle, pigs, and sheep, only one cathelicidin gene is found in humans. Interestingly, this single cathelicidin gene can be processed into different forms of antimicrobial peptides. LL-37, the most commonly studied form, is not only antimicrobial but also possesses other functional roles such as chemotaxis, apoptosis, wound healing, immune modulation, and cancer metastasis. This article reviews recent advances made in structural and biophysical studies of human LL-37 and its fragments, which serve as a basis to understand their antibacterial, anti-biofilm and antiviral activities. High-quality structures were made possible by using improved 2D NMR methods for peptide fragments and 3D NMR spectroscopy for intact LL-37. The two hydrophobic domains in the long amphipathic helix (residues 2-31) of LL-37 separated by a hydrophilic residue serine 9 explain its cooperative binding to bacterial lipopolysaccharides (LPS). Both aromatic rings (F5, F6, F17, and F27) and interfacial basic amino acids of LL-37 directly interact with anionic phosphatidylglycerols (PG). Although the peptide sequences reported in the literature vary slightly, there is a consensus that the central helix of LL-37 is essential for disrupting superbugs (e.g., MRSA), bacterial biofilms, and viruses such as human immunodeficiency virus 1 (HIV-1) and respiratory syncytial virus (RSV). In the central helix, the central arginine R23 is of particular importance in binding to bacterial membranes or DNA. Mapping the functional roles of the cationic amino acids of the major antimicrobial region of LL-37 provides a basis for designing antimicrobial peptides with desired properties. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.

Dataset Information

Anti-Staphylococcal Biofilm Effects of Human Cathelicidin Peptides.

Publications

Anti-Staphylococcal Biofilm Effects of Human Cathelicidin Peptides.

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