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

DOI: 10.1016/j.ejmech.2023.116097

Authors: Cédric Couturier (Evotec) , Quentin Ronzon (Evotec) , Giulia Lattanzi (Evotec-Aptuit (Verona) Srl) , Iain Lingard (Evotec-Aptuit (Verona) Srl) , Sebastien Coyne (Evotec) , Veronique Cazals (Evotec) , Nelly Dubarry (Evotec) , Stephane Yvon (Evotec) , Corinne Leroi-Geissler (Evotec) , Obdulia Rabal Gracia (Evotec) , Joanne Teague (Evotec) , Sylvie Sordello (Evotec) , David Corbett (Evotec) , Caroline Bauch (Evotec-Cyprotex) , Chantal Monlong (Evotec) , Lloyd Payne (Evotec; Arrepath) , Thomas Taillier (Evotec) , Hazel Fuchs (Helmholtz-Zentrum für Infektionsforschung GmbH) , Mark Broenstrup (Helmholtz-Zentrum für Infektionsforschung GmbH) , Peter H. Harrison (Wellcome Trust Centre of Human Genomics; Diamond Light Source) , Lucile Moynie (Rosalind Franklin Institute) , Abirami Lakshminarayanan (Wellcome Trust Centre of Human Genomics) , Tiberiu-Marius Gianga (Diamond Light Source) , Rohanah Hussain (Diamond Light Source) , James H. Naismith (Wellcome Trust Centre of Human Genomics; Rosalind Franklin Institute) , Michael Mourez (Evotec; Agronomical Engineering School Purpan) , Eric Bacqué (Evotec) , Fredrik Björkling (University of Copenhagen) , Jean-Francois Sabuco (Evotec) , Henrik Franzyk (University of Copenhagen)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 265

State: Published (Approved)
Published: February 2024
Diamond Proposal Number(s): 26447

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.

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: B23-Circular Dichroism

Added On: 03/01/2024 09:43

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Spectroscopy Circular Dichroism (CD)