Researchers from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the German Center for Infection Research (DZIF), in collaboration with an international team, have made significant strides in the development of a novel antibacterial treatment derived from darobactin, a naturally occurring bacterial product. The compound, which was initially discovered by researchers in the United States in 2019, demonstrates potential as an effective weapon against drug-resistant pathogens, including Escherichia coli and Acinetobacter baumannii.
Darobactin, a naturally produced antibiotic, functions by binding to an essential protein within bacterial cells, disrupting their vital processes and eventually leading to cell death. In earlier research led by Rolf Müller, Jennifer Herrmann, and colleagues, genetically engineered versions of darobactin were found to exhibit enhanced antibacterial properties. Notably, a non-natural derivative of darobactin, known as D22, demonstrated the ability to inhibit the growth of a broad range of critical pathogens in laboratory assays, suggesting its potential as a next-generation antibiotic.
In this more recent study, the research team expanded their investigation to assess the effectiveness of D22 in animal models. The compound was first tested in zebrafish embryos, where it was found to clear Acinetobacter baumannii infections with the same efficacy as ciprofloxacin, a well-established broad-spectrum antibiotic commonly used to treat complex infections. Encouraged by these promising results, the team conducted further trials in mice to evaluate the compound’s therapeutic potential in more challenging infection models.
Several important findings emerged from these trials:
1. Administration Method: D22 administered by injection was found to be more effective than oral administration, highlighting the importance of delivery method in optimizing therapeutic outcomes.
2. P. Aeruginosa Infections: In a thigh tissue infection model using Pseudomonas aeruginosa, repeated doses of D22 significantly reduced bacterial growth, although complete eradication was not achieved. This suggests that while D22 is highly effective, additional optimization may be necessary for certain bacterial strains.
3. E. coli Infections: In a severe infection model of peritonitis caused by E. coli, a regimen of four doses of D22 over 25 hours completely eradicated the infection, further underscoring the compound’s strong bactericidal activity..
4. Urinary Tract Infections: In a complicated urinary tract infection model caused by E. coli, D22 was shown to significantly reduce the bacterial load when administered twice daily for three days. However, it was not as effective as gentamicin, a widely used antibiotic, which was able to reduce the bacterial load below detectable levels.
These results demonstrate the promising antibacterial activity of D22, particularly in the treatment of infections caused by resistant pathogens. The study highlights the compound’s potential to address critical bacterial infections that have become increasingly difficult to treat due to rising antimicrobial resistance. As the researchers conclude, D22 represents an innovative approach to combating antimicrobial resistance and lays the groundwork for further development toward clinical trials. With continued research and refinement, D22 could emerge as a key therapeutic option in the ongoing fight against drug-resistant bacterial infections.
Extracted from Research Article “In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens”
published in ACS Infectious Diseases, Vol 10/Issue 12 – 20 November 2024
Keywords
antibacterial treatment, darobactin, naturally occurring bacterial product, drug-resistant pathogens, Escherichia coli, Acinetobacter baumannii, antibiotic, genetically engineered darobactin, D22, next-generation antibiotic, zebrafish embryos, ciprofloxacin, broad-spectrum antibiotic, animal models, Pseudomonas aeruginosa, antimicrobial resistance, therapeutic potential, clinical trials, drug-resistant bacterial infections