In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens.

Autor:	Kany AM; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany., Fries F; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany.; Department of Pharmacy, Saarland University, Saarbrücken 66123, Germany.; Deutsches Zentrum für Infektionsforschung (DZIF) e.V., Braunschweig 38124, Germany., Seyfert CE; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany., Porten C; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany.; Department of Pharmacy, Saarland University, Saarbrücken 66123, Germany.; Deutsches Zentrum für Infektionsforschung (DZIF) e.V., Braunschweig 38124, Germany., Deckarm S; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany.; Department of Pharmacy, Saarland University, Saarbrücken 66123, Germany.; Deutsches Zentrum für Infektionsforschung (DZIF) e.V., Braunschweig 38124, Germany., Chacón Ortiz M; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany., Dubarry N; Evotec, Lyon 69007, France., Vaddi S; Evotec, Alderly Park SK10 4TG, United Kingdom., Große M; Helmholtz Centre for Infection Research (HZI), Department Microbial Drugs, Braunschweig 38124, Germany., Bernecker S; Helmholtz Centre for Infection Research (HZI), Department Microbial Drugs, Braunschweig 38124, Germany., Sandargo B; Helmholtz Centre for Infection Research (HZI), Department Microbial Drugs, Braunschweig 38124, Germany., Müller AV; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany.; Department of Pharmacy, Saarland University, Saarbrücken 66123, Germany.; Deutsches Zentrum für Infektionsforschung (DZIF) e.V., Braunschweig 38124, Germany., Bacqué E; Evotec, Marcy L'Etoile 69280, France., Stadler M; Helmholtz Centre for Infection Research (HZI), Department Microbial Drugs, Braunschweig 38124, Germany.; Institute of Microbiology, Technische Universität Braunschweig, Braunschweig 38106, Germany., Herrmann J; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany.; Deutsches Zentrum für Infektionsforschung (DZIF) e.V., Braunschweig 38124, Germany., Müller R; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarbrücken 66123, Germany.; Department of Pharmacy, Saarland University, Saarbrücken 66123, Germany.; Deutsches Zentrum für Infektionsforschung (DZIF) e.V., Braunschweig 38124, Germany.; Helmholtz International Lab for Anti-infectives, Saarbrücken 66123, Germany.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2024 Dec 13; Vol. 10 (12), pp. 4337-4346. Date of Electronic Publication: 2024 Nov 20.
DOI:	10.1021/acsinfecdis.4c00687
Abstrakt:	In recent years, naturally occurring darobactins have emerged as a promising compound class to combat infections caused by critical Gram-negative pathogens. In this study, we describe the in vivo evaluation of derivative D22, a non-natural biosynthetic darobactin analogue with significantly improved antibacterial activity. We found D22 to be active in vivo against key critical Gram-negative human pathogens, as demonstrated in murine models of Pseudomonas aeruginosa thigh infection, Escherichia coli peritonitis/sepsis, and urinary tract infection (UTI). Furthermore, we observed the restored survival of Acinetobacter baumannii -infected embryos in a zebrafish infection model. These in vivo proof-of-concept (PoC) in diverse models of infection against highly relevant pathogens, including drug-resistant isolates, highlight the versatility of darobactins in the treatment of bacterial infections and show superiority of D22 over the natural darobactin A. Together with a favorable safety profile, these findings pave the way for further optimization of the darobactin scaffold toward the development of a novel antibiotic.
Databáze:	MEDLINE
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