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Antibacterial medications play a vital role in the treatment of infections. However, the rising issue of bacteria becoming resistant to existing drugs—rendering them less effective or completely ineffective—highlights the urgent need for new therapies. Researchers have explored a promising antibacterial treatment derived from a modified version of darobactin, a substance that originates from a bacterium. The research team has reported successful proof-of-concept trials in animals infected with bacteria like E. coli, which is known for developing resistance to drugs.
Antibacterial medications are crucial for managing infections. However, the growing challenge of bacterial resistance to existing treatments—leading to reduced effectiveness or total ineffectiveness—underscores the urgent demand for new drugs. Building on previous research, scientists in ACS Infectious Diseases have showcased a potential antibacterial treatment developed from a modified darobactin, a compound sourced from bacteria. The team has published results from proof-of-concept animal studies concerning infections caused by drug-resistant bacteria, including E. coli.
This research was released during the World Health Organization’s World Antimicrobial Resistance (AMR) Awareness Week, which takes place from November 18 to 24.
Earlier in 2024, the World Health Organization revised its list of bacterial pathogens known to develop resistance to antibiotics, which now includes Acinetobacter baumannii, Pseudomonas aeruginosa, and E. coli, among others. Despite the pressing need for new antibiotics targeting these key pathogens, there are few viable candidates available. One promising resistance-fighting compound is darobactin, an antibiotic found naturally in a bacterium. Darobactin binds to a critical protein in the cells of various bacteria, ultimately leading to their death. Previously, Rolf Müller, Jennifer Herrmann, and their team demonstrated that genetically altered versions of darobactin possess antibacterial properties. Notably, one of these synthetic darobactins, termed D22, effectively inhibited the growth of A. baumannii in laboratory tests.
In this latest study, a larger group led by Müller and Herrmann evaluated the effectiveness of the engineered D22 compound against several prioritized bacterial infections in animal subjects. First, they tested D22 on zebrafish embryos, where it successfully eradicated A. baumannii infection with the same efficiency as ciprofloxacin, a broad-spectrum antibiotic used for complex infections. Subsequently, the team conducted a range of efficacy and dosage studies using mice:
- Optimal delivery method: The findings suggested that administering D22 through injection produced better results compared to oral delivery.
- Efficacy against P. aeruginosa: Multiple doses of D22 significantly curtailed P. aeruginosa bacterial growth in mice (in thigh tissue) but did not completely eliminate the infection.
- Multi-dose experiments against E. coli: Delivering D22 four times within 25 hours completely eliminated E. coli in a severe infection model for peritonitis (abdomen infection). Single doses also showed promising activity. When D22 was injected twice daily over three days, there was a marked reduction in bacterial levels for complicated E. coli urinary tract infections, although not to the extent seen with gentamicin, which managed to lower bacterial loads to undetectable levels.
These findings indicate that D22 can effectively combat serious infections, emphasizing the potential of this compound for further advancement toward future clinical trials as “an innovative strategy to tackle antimicrobial resistance,” as noted by the researchers.
The authors express gratitude for funding from the Helmholtz Impuls- und Vernetzungsfonds (Impulse and Networking Fund).
Several authors are affiliated with Evotec, a biotech firm focused on drug discovery and development.
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