Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria
Antimicrobial resistance poses a major threat to public health. Given the paucity of novel antimicrobials to treat resistant infections, the emergence of multidrug-resistant bacteria renewed interest in antimicrobial peptides as potential therapeutics. This study designed a new analog of the antimic...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Antibiotics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2079-6382/12/2/391 |
| _version_ | 1827758964411990016 |
|---|---|
| author | Gabriela Marinho Righetto José Luiz de Souza Lopes Paulo José Martins Bispo Camille André Julia Medeiros Souza Adriano Defini Andricopulo Leila Maria Beltramini Ilana Lopes Baratella da Cunha Camargo |
| author_facet | Gabriela Marinho Righetto José Luiz de Souza Lopes Paulo José Martins Bispo Camille André Julia Medeiros Souza Adriano Defini Andricopulo Leila Maria Beltramini Ilana Lopes Baratella da Cunha Camargo |
| author_sort | Gabriela Marinho Righetto |
| collection | DOAJ |
| description | Antimicrobial resistance poses a major threat to public health. Given the paucity of novel antimicrobials to treat resistant infections, the emergence of multidrug-resistant bacteria renewed interest in antimicrobial peptides as potential therapeutics. This study designed a new analog of the antimicrobial peptide Plantaricin 149 (Pln149-PEP20) based on previous Fmoc-peptides. The minimal inhibitory concentrations of Pln149-PEP20 were determined for 60 bacteria of different species and resistance profiles, ranging from 1 mg/L to 128 mg/L for Gram-positive bacteria and 16 to 512 mg/L for Gram-negative. Furthermore, Pln149-PEP20 demonstrated excellent bactericidal activity within one hour. To determine the propensity to develop resistance to Pln149-PEP20, a directed-evolution in vitro experiment was performed. Whole-genome sequencing of selected mutants with increased MICs and wild-type isolates revealed that most mutations were concentrated in genes associated with membrane metabolism, indicating the most likely target of Pln149-PEP20. Synchrotron radiation circular dichroism showed how this molecule disturbs the membranes, suggesting a carpet mode of interaction. Membrane depolarization and transmission electron microscopy assays supported these two hypotheses, although a secondary intracellular mechanism of action is possible. The molecule studied in this research has the potential to be used as a novel antimicrobial therapy, although further modifications and optimization remain possible. |
| first_indexed | 2024-03-11T09:15:01Z |
| format | Article |
| id | doaj.art-5ea26b3cbc744a11b6e6a5110858fbec |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T09:15:01Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-5ea26b3cbc744a11b6e6a5110858fbec2023-11-16T18:44:23ZengMDPI AGAntibiotics2079-63822023-02-0112239110.3390/antibiotics12020391Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant BacteriaGabriela Marinho Righetto0José Luiz de Souza Lopes1Paulo José Martins Bispo2Camille André3Julia Medeiros Souza4Adriano Defini Andricopulo5Leila Maria Beltramini6Ilana Lopes Baratella da Cunha Camargo7Laboratory of Molecular Epidemiology and Microbiology, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, BrazilLaboratory of Applied Biophysics, Department of Applied Physics, Institute of Physics, University of São Paulo, São Paulo 05315-970, BrazilDepartment of Ophthalmology, Infectious Disease Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02115, USADepartment of Ophthalmology, Infectious Disease Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02115, USALaboratory of Medicinal and Computational Chemistry, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, BrazilLaboratory of Medicinal and Computational Chemistry, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, BrazilGroup of Biophysics and Structural Biology “Sérgio Mascarenhas”, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, BrazilLaboratory of Molecular Epidemiology and Microbiology, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, BrazilAntimicrobial resistance poses a major threat to public health. Given the paucity of novel antimicrobials to treat resistant infections, the emergence of multidrug-resistant bacteria renewed interest in antimicrobial peptides as potential therapeutics. This study designed a new analog of the antimicrobial peptide Plantaricin 149 (Pln149-PEP20) based on previous Fmoc-peptides. The minimal inhibitory concentrations of Pln149-PEP20 were determined for 60 bacteria of different species and resistance profiles, ranging from 1 mg/L to 128 mg/L for Gram-positive bacteria and 16 to 512 mg/L for Gram-negative. Furthermore, Pln149-PEP20 demonstrated excellent bactericidal activity within one hour. To determine the propensity to develop resistance to Pln149-PEP20, a directed-evolution in vitro experiment was performed. Whole-genome sequencing of selected mutants with increased MICs and wild-type isolates revealed that most mutations were concentrated in genes associated with membrane metabolism, indicating the most likely target of Pln149-PEP20. Synchrotron radiation circular dichroism showed how this molecule disturbs the membranes, suggesting a carpet mode of interaction. Membrane depolarization and transmission electron microscopy assays supported these two hypotheses, although a secondary intracellular mechanism of action is possible. The molecule studied in this research has the potential to be used as a novel antimicrobial therapy, although further modifications and optimization remain possible.https://www.mdpi.com/2079-6382/12/2/391Plantaricin 149synergismcarpet-like mechanism |
| spellingShingle | Gabriela Marinho Righetto José Luiz de Souza Lopes Paulo José Martins Bispo Camille André Julia Medeiros Souza Adriano Defini Andricopulo Leila Maria Beltramini Ilana Lopes Baratella da Cunha Camargo Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria Antibiotics Plantaricin 149 synergism carpet-like mechanism |
| title | Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria |
| title_full | Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria |
| title_fullStr | Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria |
| title_full_unstemmed | Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria |
| title_short | Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria |
| title_sort | antimicrobial activity of an fmoc plantaricin 149 derivative peptide against multidrug resistant bacteria |
| topic | Plantaricin 149 synergism carpet-like mechanism |
| url | https://www.mdpi.com/2079-6382/12/2/391 |
| work_keys_str_mv | AT gabrielamarinhorighetto antimicrobialactivityofanfmocplantaricin149derivativepeptideagainstmultidrugresistantbacteria AT joseluizdesouzalopes antimicrobialactivityofanfmocplantaricin149derivativepeptideagainstmultidrugresistantbacteria AT paulojosemartinsbispo antimicrobialactivityofanfmocplantaricin149derivativepeptideagainstmultidrugresistantbacteria AT camilleandre antimicrobialactivityofanfmocplantaricin149derivativepeptideagainstmultidrugresistantbacteria AT juliamedeirossouza antimicrobialactivityofanfmocplantaricin149derivativepeptideagainstmultidrugresistantbacteria AT adrianodefiniandricopulo antimicrobialactivityofanfmocplantaricin149derivativepeptideagainstmultidrugresistantbacteria AT leilamariabeltramini antimicrobialactivityofanfmocplantaricin149derivativepeptideagainstmultidrugresistantbacteria AT ilanalopesbaratelladacunhacamargo antimicrobialactivityofanfmocplantaricin149derivativepeptideagainstmultidrugresistantbacteria |