In a significant advancement, a modified darobactin compound has shown promise in treating drug-resistant bacterial infections in animal models, offering a potential new weapon against pathogens like E. coli that increasingly evade current antibiotics.
Antibacterial drugs are essential for treating infections, but the growing problem of bacterial resistance has rendered many current treatments less effective or even useless. This has created an urgent need for new solutions.
Researchers publishing in ACS Infectious Diseases have developed a modified version of darobactin, a compound originally derived from bacteria, showing promise as a potential antibacterial treatment. In proof-of-concept animal trials, the modified compound demonstrated effectiveness against drug-resistant bacteria, including E. coli.
This research was released during the World Health Organization’s World Antimicrobial Resistance (AMR) Awareness Week, observed from November 18 to 24.
The Threat of Antibiotic Resistance
Earlier in 2024, the World Health Organization updated its list of bacterial pathogens that can develop resistance to antibiotics to include Acinetobacter baumannii, Pseudomonas aeruginosa, and E. coli, among others. Despite the need for new antibiotics that target these priority pathogens, scientists don’t have many candidates. One potential resistance-breaking compound is called darobactin, a naturally produced antibiotic discovered in a bacterium. Darobactin binds to an essential protein in cells of different bacteria and eventually causes their death. Previously, Rolf Müller, Jennifer Herrmann, and colleagues showed that genetically engineered versions of darobactin have antibacterial activity. Specifically, one of these non-natural, biosynthetic darobactins (called D22) inhibited A. baumannii growth in lab assays.
Advancements in Darobactin Research
For this new study, a larger team led by Müller and Herrmann tested the engineered D22 compound against several priority bacterial infections in animals. First, in zebrafish embryos, D22 treatment cleared A. baumannii infection as effectively as ciprofloxacin, a broad-spectrum antibiotic used for complicated infections. Then the team conducted a series of efficacy and dosing trials with mice:
- Best delivery method: Observations indicated that administering D22 as an injection was more effective than via mouth.
- Efficacy against P. aeruginosa: Repeated doses of D22 substantially limited P. aeruginosa bacterial growth in mice (thigh tissue infection) but didn’t fully clear the infection.
- Multi-dose experiments against E. coli: Administering D22 four times in 25 hours fully cleared E. coli in a severe infection model of peritonitis (abdomen infection). Activity was also observed for single doses. Twice-daily D22 injections over three days significantly reduced bacterial presence in a complicated E. coli urinary tract infection, although not as low as the antibiotic gentamicin, which reduced bacterial loads below detection.
Promising Outcomes and Future Directions
These results show that D22 can inhibit critical infections and highlight the compound’s promise for further development toward future clinical trials as “an innovative solution to fight antimicrobial resistance,” say the researchers.
Reference: “In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens” by Andreas M. Kany, Franziska Fries, Carsten E. Seyfert, Christoph Porten, Selina Deckarm, María Chacón Ortiz, Nelly Dubarry, Swapna Vaddi, Miriam Große, Steffen Bernecker, Birthe Sandargo, Alison V. Müller, Eric Bacqué, Marc Stadler, Jennifer Herrmann and Rolf Müller, 20 November 2024, ACS Infectious Diseases.
DOI: 10.1021/acsinfecdis.4c00687
The authors acknowledge funding from the Helmholtz Impuls- und Vernetzungsfonds (Impulse and Networking Fund).
Some of the authors are employees of Evotec, a biotechnology company involved in drug discovery and development.
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