Antimicrobial and Antibiofilm Activities of Helical Antimicrobial Peptide Sequences Incorporating Metal-Binding Motifs
| Autor: | Marlon H. Cardoso, Alfredo M. Angeles-Boza, Danieli Fernanda Buccini, Octavio L. Franco, Justice Kwabena Sarfo, Caleb M Agbale, Isaac K. A. Galyuon, Marcelo D. T. Torres, Cesar de la Fuente-Nunez, Samuel A. Juliano, Gislaine Greice Oliveira Silva |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Methicillin-Resistant Staphylococcus aureus Protein Conformation alpha-Helical Membrane permeability Stereochemistry Antimicrobial peptides Peptide Microbial Sensitivity Tests Molecular Dynamics Simulation Protein Engineering medicine.disease_cause Hemolysis Biochemistry 03 medical and health sciences Protein structure Escherichia coli medicine Animals Amino Acid Sequence Peptide sequence Chelating Agents chemistry.chemical_classification Mice Inbred BALB C 0303 health sciences Chemistry 030302 biochemistry & molecular biology Drug Synergism Protein engineering Antimicrobial Anti-Bacterial Agents Klebsiella pneumoniae Biofilms Pseudomonas aeruginosa Carrier Proteins Gram-Negative Bacterial Infections Copper Antimicrobial Cationic Peptides |
| Zdroj: | Biochemistry. 58:3802-3812 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/acs.biochem.9b00440 |
| Popis: | Antimicrobial peptides (AMPs) represent alternative strategies to combat the global health problem of antibiotic resistance. However, naturally occurring AMPs are generally not sufficiently active for use as antibiotics. Optimized synthetic versions incorporating additional design principles are needed. Here, we engineered amino-terminal Cu(II) and Ni(II) (ATCUN) binding motifs, which can enhance biological function, into the native sequence of two AMPs, CM15 and citropin1.1. The incorporation of metal-binding motifs modulated the antimicrobial activity of synthetic peptides against a panel of carbapenem-resistant enterococci (CRE) bacteria, including carbapenem-resistant Klebsiella pneumoniae (KpC+) and Escherichia coli (KpC+). Activity modulation depended on the type of ATCUN variant utilized. Membrane permeability assays revealed that the in silico selected lead template, CM15, and its ATCUN analogs increased bacterial cell death. Mass spectrometry, circular dichroism, and molecular dynamics simulations indicated that coordinating ATCUN derivatives with Cu(II) ions did not increase the helical tendencies of the AMPs. CM15 ATCUN variants, when combined with Meropenem, streptomycin, or chloramphenicol, showed synergistic effects against E. coli (KpC+ 1812446) biofilms. Motif addition also reduced the hemolytic activity of the wild-type AMP and improved the survival rate of mice in a systemic infection model. The dependence of these bioactivities on the particular amino acids of the ATCUN motif highlights the possible use of size, charge, and hydrophobicity to fine-tune AMP biological function. Our data indicate that incorporating metal-binding motifs into peptide sequences leads to synthetic variants with modified biological properties. These principles may be applied to augment the activities of other peptide sequences. |
| Databáze: | OpenAIRE |
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