Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria
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
Affiliations
Gabriela Marinho Righetto
Laboratory of Molecular Epidemiology and Microbiology, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, Brazil
José Luiz de Souza Lopes
Laboratory of Applied Biophysics, Department of Applied Physics, Institute of Physics, University of São Paulo, São Paulo 05315-970, Brazil
Paulo José Martins Bispo
Department of Ophthalmology, Infectious Disease Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02115, USA
Camille André
Department of Ophthalmology, Infectious Disease Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA 02115, USA
Julia Medeiros Souza
Laboratory of Medicinal and Computational Chemistry, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, Brazil
Adriano Defini Andricopulo
Laboratory of Medicinal and Computational Chemistry, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, Brazil
Leila Maria Beltramini
Group 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, Brazil
Ilana Lopes Baratella da Cunha Camargo
Laboratory of Molecular Epidemiology and Microbiology, Department of Physics and Interdisciplinary Science, São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, Brazil
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.
