Antimicrobial Activity of an Fmoc-Plantaricin 149 Derivative Peptide against Multidrug-Resistant Bacteria

• Published in: Antibiotics (Basel) 2023-02, Vol.12 (2), p.391
• Main Authors: Righetto, Gabriela Marinho, Lopes, José Luiz de Souza, Bispo, Paulo José Martins, André, Camille, Souza, Julia Medeiros, Andricopulo, Adriano Defini, Beltramini, Leila Maria, Camargo, Ilana Lopes Baratella da Cunha
• Format: Article
• Language: English
• Subjects: Antibiotics; Antimicrobial activity; Antimicrobial agents; Antimicrobial peptides; Antimicrobial resistance; Bacteria; Bactericidal activity; Biomass; Cancer; carpet-like mechanism; Circular dichroism; Cytotoxicity; Depolarization; Dichroism; Drug resistance; Drug resistance in microorganisms; Evolution; Gene sequencing; Genomes; Gram-negative bacteria; Gram-positive bacteria; Health aspects; Health risks; Membrane potential; Membranes; Metabolism; Multidrug resistance; Mutation; Optimization; Peptides; Plantaricin 149; Public health; Radiation; Staphylococcus infections; Synchrotron radiation; Synchrotrons; synergism; Transmission electron microscopy; Whole genome sequencing
• ISSN: 2079-6382; 2079-6382
• DOI: 10.3390/antibiotics12020391

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.