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

Autor: Couturier C; Evotec, 1541, Avenue Marcel Mérieux, 69280, Marcy L'Etoile, France. Electronic address: cedric.couturier@evotec.com., Ronzon Q; Evotec, 1541, Avenue Marcel Mérieux, 69280, Marcy L'Etoile, France., Lattanzi G; Evotec-Aptuit (Verona) Srl, Via Alessandro Fleming 4, 37135, Verona, Italy., Lingard I; Evotec-Aptuit (Verona) Srl, Via Alessandro Fleming 4, 37135, Verona, Italy., Coyne S; Evotec, 40 Avenue Tony Garnier, 69007, Lyon, France., Cazals V; Evotec, 40 Avenue Tony Garnier, 69007, Lyon, France., Dubarry N; Evotec, 40 Avenue Tony Garnier, 69007, Lyon, France., Yvon S; Evotec, 40 Avenue Tony Garnier, 69007, Lyon, France., Leroi-Geissler C; Evotec, 40 Avenue Tony Garnier, 69007, Lyon, France., Gracia OR; Evotec, 195, Route D'Espagne, 31100, Toulouse, France., Teague J; Evotec, No. 23F, Mereside, Alderley Park, Cheshire, SK10 4TG, United Kingdom., Sordello S; Evotec, 195, Route D'Espagne, 31100, Toulouse, France., Corbett D; Evotec, No. 23F, Mereside, Alderley Park, Cheshire, SK10 4TG, United Kingdom., Bauch C; Evotec-Cyprotex, No. 24, Mereside, Alderley Park, Cheshire, SK10 4TG, United Kingdom., Monlong C; Evotec, 40 Avenue Tony Garnier, 69007, Lyon, France., Payne L; Evotec, No. 23F, Mereside, Alderley Park, Cheshire, SK10 4TG, United Kingdom., Taillier T; Evotec, 195, Route D'Espagne, 31100, Toulouse, France., Fuchs H; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstraße 7, 38124, Braunschweig, Germany., Broenstrup M; Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstraße 7, 38124, Braunschweig, Germany., Harrison PH; Division of Structural Biology, Wellcome Trust Centre of Human Genomics, 7 Roosevelt Drive, Oxford, OX3 7BN, United Kingdom., Moynié L; Rosalind Franklin Institute, Harwell Science and Innovation Campus, Didcot, OX11 0QS, United Kingdom., Lakshminarayanan A; Division of Structural Biology, Wellcome Trust Centre of Human Genomics, 7 Roosevelt Drive, Oxford, OX3 7BN, United Kingdom., Gianga TM; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, United Kingdom., Hussain R; Diamond Light Source Ltd., Harwell Science and Innovation Campus, Didcot, OX11 0DE, United Kingdom., Naismith JH; 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., Mourez M; Evotec, 40 Avenue Tony Garnier, 69007, Lyon, France., Bacqué E; Evotec, 1541, Avenue Marcel Mérieux, 69280, Marcy L'Etoile, France., Björkling F; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100, Denmark., Sabuco JF; Evotec, 1541, Avenue Marcel Mérieux, 69280, Marcy L'Etoile, France., Franzyk H; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 162, DK-2100, Denmark.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Feb 05; Vol. 265, pp. 116097. Date of Electronic Publication: 2023 Dec 23.
DOI: 10.1016/j.ejmech.2023.116097
Abstrakt: 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 TriA 1 (termed H-TriA 1 ) 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-TriA 1 ) 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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