In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens
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 <i>Pseudomonas aeruginosa</i> thigh infection, <i>Escherichia coli</i> peritonitis/sepsis, and urinary tract infection (UTI). Furthermore, we observed the restored survival of <i>Acinetobacter baumannii</i>-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.
Authors
- Nelly Dubarry
- Christoph Porten (ORCID: https://orcid.org/0000-0002-7177-2783)
- Carsten E. Seyfert (ORCID: https://orcid.org/0000-0001-7433-5290)
- Marc Stadler (ORCID: https://orcid.org/0000-0002-7284-8671)
- Andreas M. Kany (ORCID: https://orcid.org/0000-0001-7580-3658)
- Miriam Große (ORCID: https://orcid.org/0000-0001-5972-639X)
- Selina Deckarm (ORCID: https://orcid.org/0000-0003-1678-8018)
- M.C. Ortiz
- Franziska Fries (ORCID: https://orcid.org/0009-0009-6485-8317)
- Eric Bacqué (ORCID: https://orcid.org/0000-0002-9339-5050)
- Rolf Müller (ORCID: https://orcid.org/0000-0002-1042-5665)
- Birthe Sandargo (ORCID: https://orcid.org/0009-0007-2193-1874)
- Jennifer E. Herrmann (ORCID: https://orcid.org/0000-0003-3398-9938)
- Steffen Bernecker
- Swapna Vaddi
- Alison V. Müller
Institutions
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Center for Information Security (DE)
- German Central Institute for Social Issues (DE)
- Helmholtz Institute for Pharmaceutical Research Saarland (DE)
- Evotec (United Kingdom) (GB)
- Saarland University (DE)
- Technische Universität Braunschweig (DE)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1021/acsinfecdis.4c00687
- Citations
- 9
- Primary Topic
- Bacterial Identification and Susceptibility Testing
- Type
- article
- Field-Weighted Citation Impact
- 3.43
Funders
- Deutsches Zentrum für Infektionsforschung
- Helmholtz-Gemeinschaft
- Universität des Saarlandes