Optimization of the Antibacterial Spectrum and the Developability Profile of the Novel-Class Natural Product Corramycin.

Autor:	Renard S; Evotec, 40 Avenue Tony Garnier, Lyon 69007, France., Versluys S; Evotec, 195, Route d'Espagne, Toulouse 31100, France., Taillier T; Evotec, 1541, Avenue Marcel Mérieux, Marcy L'Etoile 69280, France., Dubarry N; Evotec, 40 Avenue Tony Garnier, Lyon 69007, France., Leroi-Geissler C; Evotec, 40 Avenue Tony Garnier, Lyon 69007, France., Rey A; Evotec, 1541, Avenue Marcel Mérieux, Marcy L'Etoile 69280, France., Cornaire E; Evotec, 1541, Avenue Marcel Mérieux, Marcy L'Etoile 69280, France., Sordello S; Evotec, 195, Route d'Espagne, Toulouse 31100, France., Carry JB; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Angouillant-Boniface O; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Gouyon T; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Thompson F; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Lebourg G; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Certal V; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Balazs L; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Arranz E; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Doerflinger G; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Bretin F; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Gervat V; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Brohan E; Sanofi, 13 Quai Jules Guesde, Vitry-sur-Seine 94403, France., Kraft V; Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, Frankfurt am Main 65926, Germany., Boulenc X; Evotec, 40 Avenue Tony Garnier, Lyon 69007, France., Ducelier C; Sanofi, 1 Avenue Pierre Brossolette, Chilly-Mazarin 91385, France., Bacqué E; Evotec, 1541, Avenue Marcel Mérieux, Marcy L'Etoile 69280, France., Couturier C; Evotec, 1541, Avenue Marcel Mérieux, Marcy L'Etoile 69280, France.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Dec 28; Vol. 66 (24), pp. 16869-16887. Date of Electronic Publication: 2023 Dec 13.
DOI:	10.1021/acs.jmedchem.3c01564
Abstrakt:	Corramycin 1 is a novel zwitterionic antibacterial peptide isolated from a culture of the myxobacterium Corallococcus coralloides . Though Corramycin displayed a narrow spectrum and modest MICs against sensitive bacteria, its ADMET and physchem profile as well as its high tolerability in mice along with an outstanding in vivo efficacy in an Escherichia coli septicemia mouse model were promising and prompted us to embark on an optimization program aiming at enlarging the spectrum and at increasing the antibacterial activities by modulating membrane permeability. Scanning the peptidic moiety by the Ala-scan strategy followed by key stabilization and introduction of groups such as a primary amine or siderophore allowed us to enlarge the spectrum and increase the overall developability profile. The optimized Corramycin 28 showed an improved mouse IV PK and a broader spectrum with high potency against key Gram-negative bacteria that translated into excellent efficacy in several in vivo mouse infection models.
Databáze:	MEDLINE
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