An innovative class of antibiotics to combat drug-resistant bacteria
New active compounds inspired by a bacterium
A three-dimensional computer-generated image of the multi-resistant bacterium Pseudomonas aeruginosa, based on scanning electron microscope images.
Antibacterial drugs are important for treating infections. However, increasing bacterial resistance to current drugs—making them ineffective or only partially effective—means that new drugs are urgently needed. Building on previous work, researchers from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the German Center for Infection Research (DZIF), together with an international team of collaborators, have demonstrated a potential antibacterial treatment from a biosynthetic derivative of darobactin, a bacterial natural product. The team reports proof-of-concept animal studies in infections caused by bacteria including Escherichia coli and Acinetobacter baumannii, which are known to develop drug resistance. The study was published in the journal ACS Infectious Diseases during World Antimicrobial Resistance (AMR) Awareness Week (November 18-24).
In 2024, the World Health Organisation updated its list of bacterial pathogens that can develop resistance to antibiotics to include E. coli, A. baumannii and Pseudomonas aeruginosa, among others. Despite the need for new antibiotics targeting these priority pathogens, scientists do not have many candidates in (pre-)clinical development. One potential resistance-breaking compound is darobactin, a naturally occurring antibiotic first discovered in a bacterium by researchers in the US in 2019. Darobactin binds to an essential protein in bacterial cells and eventually causes them to die. Previously, the team around the DZIF scientists Rolf Müller and Jennifer Herrmann found that genetically engineered versions of darobactin had superior antibacterial activity. Specifically, a non-natural darobactin derivative (D22) inhibited growth of all the critical pathogens mentioned above in lab tests.
For this new study, a larger team led by Müller and Herrmann tested the engineered 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. They then carried out a series of efficacy and dosing studies in mice:
- Best delivery method: Observations indicated that D22 given by injection was more effective than oral administration.
- Efficacy against P. aeruginosa: Repeated doses of D22 significantly reduced the growth of P. aeruginosa bacteria in mice (thigh tissue infection), but did not completely eradicate the infection.
- Multi-dose drug tests on E. coli: Four doses of D22 over 25 hours completely eradicated E. coli in a severe infection model of peritonitis. Very good activity was also observed for single doses. D22 injected twice daily for three days significantly reduced the bacterial load in a complicated E. coli urinary tract infection, although not as effectively as the antibiotic gentamicin, which reduced the bacterial load below detection.
These results show how D22 can inhibit critical infections and highlight the compound’s promise for further development towards future clinical trials as “an innovative solution to fight antimicrobial resistance,” the researchers said.
The authors acknowledge funding from the Impulse and Networking Fund (Impuls- und Vernetzungsfonds) of the Helmholtz Association. Some of the authors are employees of Evotec, a biotechnology company engaged in drug discovery and development.
Source: Press release of the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)
More information on AMR research at the DZIF can be found in the DZIF press release World AMR Awareness Week 2024, 18-24 November – Educate. Advocate. Act now.
