This week is World Health Organization’s (WHO) World Antimicrobial Resistance (AMR) Awareness Week, bringing attention to the urgent need for new antibacterial drugs. A new study reports that researchers have demonstrated that a modified darobactin—a compound derived originally from a bacterium—is a potential antibacterial treatment. The team reports proof-of-concept animal trials on infections caused by bacteria that are known to develop drug resistance.
This work is published in ACS Infectious Diseases in the paper, “In Vivo Activity Profiling of Biosynthetic Darobactin D22 against Critical Gram-Negative Pathogens.”
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.
One potential resistance-breaking compound is darobactin, a novel class of antibiotic natural compounds originally discovered from the entomopathogenic bacterium Photorhabdus khanii HGB1456. Darobactins act on the transmembrane protein BamA. Inhibition of this outer membrane protein by darobactin, the authors note, results in insufficient folding and insertion of proteins into the outer membrane, eventually leading to cell death.
Previously, researchers showed that genetically engineered versions of darobactin have antibacterial activity. Specifically, one of these non-natural, biosynthetic darobactins (D22) inhibited A. baumannii growth in lab assays.
For this new study, a team tested the engineered D22 compound against several priority bacterial infections in animals. In zebrafish embryos, D22 treatment cleared A. baumannii infections as effectively as the broad spectrum antibiotic ciprofloxacin.
The team also conducted a series of efficacy and dosing trials with mice and found that administering D22 as an injection was more effective than through the mouth. The findings also suggest that repeated doses of D22 substantially limited P. aeruginosa bacterial growth in mice—in a thigh tissue infection—but didn’t fully clear the infection.
In multi-dose experiments against E. coli, the data show that 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.
These results show that D22 can inhibit critical infections and highlights the compound’s promise for further development toward future clinical trials as “an innovative solution to fight antimicrobial resistance,” say the researchers.
