2. Academic Validation
  3. Studies of antibacterial activity (in vitro and in vivo) and mode of action for des-acyl tridecaptins (DATs)

Studies of antibacterial activity (in vitro and in vivo) and mode of action for des-acyl tridecaptins (DATs)

  • Eur J Med Chem. 2024 Feb 5:265:116097. doi: 10.1016/j.ejmech.2023.116097.
Cédric Couturier 1,  Quentin Ronzon 2,  Giulia Lattanzi 3,  Iain Lingard 3,  Sebastien Coyne 4,  Veronique Cazals 4,  Nelly Dubarry 4,  Stephane Yvon 4,  Corinne Leroi-Geissler 4,  Obdulia Rabal Gracia 5,  Joanne Teague 6,  Sylvie Sordello 5,  David Corbett 6,  Caroline Bauch 7,  Chantal Monlong 4,  Lloyd Payne 6,  Thomas Taillier 5,  Hazel Fuchs 8,  Mark Broenstrup 8,  Peter H Harrison 9,  Lucile Moynié 10,  Abirami Lakshminarayanan 9,  Tiberiu-Marius Gianga 11,  Rohanah Hussain 11,  James H Naismith 12,  Michael Mourez 4,  Eric Bacqué 2,  Fredrik Björkling 13,  Jean-Francois Sabuco 2,  Henrik Franzyk 13
Affiliations

Affiliations

  • 1 Evotec, 1541, Avenue Marcel Mérieux, 69280, Marcy L'Etoile, France. Electronic address: [email protected].
  • 2 Evotec, 1541, Avenue Marcel Mérieux, 69280, Marcy L'Etoile, France.
  • 3 Evotec-Aptuit (Verona) Srl, Via Alessandro Fleming 4, 37135, Verona, Italy.
  • 4 Evotec, 40 Avenue Tony Garnier, 69007, Lyon, France.
  • 5 Evotec, 195, Route D'Espagne, 31100, Toulouse, France.
  • 6 Evotec, No. 23F, Mereside, Alderley Park, Cheshire, SK10 4TG, United Kingdom.
  • 7 Evotec-Cyprotex, No. 24, Mereside, Alderley Park, Cheshire, SK10 4TG, United Kingdom.
  • 8 Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstraße 7, 38124, Braunschweig, Germany.
  • 9 Division of Structural Biology, Wellcome Trust Centre of Human Genomics, 7 Roosevelt Drive, Oxford, OX3 7BN, United Kingdom.
  • 10 Rosalind Franklin Institute, Harwell Science and Innovation Campus, Didcot, OX11 0QS, United Kingdom.
  • 11 Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, United Kingdom.
  • 12 Division of Structural Biology, Wellcome Trust Centre of Human Genomics, 7 Roosevelt Drive, Oxford, OX3 7BN, United Kingdom; Rosalind Franklin Institute, Harwell Science and Innovation Campus, Didcot, OX11 0QS, United Kingdom.
  • 13 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100, Denmark.
PMID: 38157595 DOI: 10.1016/j.ejmech.2023.116097
Abstract

Tridecaptins comprise a class of linear cationic lipopeptides with an N-terminal fatty acyl moiety. These 13-mer antimicrobial peptides consist of a combination of d- and l-amino acids, conferring increased proteolytic stability. Intriguingly, they are biosynthesized by non-ribosomal peptide synthetases in the same Bacterial species that also produce the cyclic polymyxins displaying similar fatty acid tails. Previously, the des-acyl analog of TriA1 (termed H-TriA1) was found to possess very weak Antibacterial activity, albeit it potentiated the effect of several Antibiotics. In the present study, two series of des-acyl tridecaptins were explored with the aim of improving the direct Antibacterial effect. At the same time, overall physico-chemical properties were modulated by amino acid substitution(s) to diminish the risk of undesired levels of hemolysis and to avoid an impairment of mammalian cell viability, since these properties are typically associated with highly hydrophobic cationic peptides. Microbiology and biophysics tools were used to determine Bacterial uptake, while circular dichroism and isothermal calorimetry were used to probe the mode of action. Several analogs had improved Antibacterial activity (as compared to that of H-TriA1) against Enterobacteriaceae. Optimization enabled identification of the lead compound 29 that showed a good ADMET profile as well as in vivo efficacy in a variety of mouse models of Infection.

Keywords

Antibiotic; Antimicrobial peptides; Gram-negative bacteria; Solid-phase peptide synthesis; Structure-activity relationships; tridecaptins.

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