More and more bacterial agents of infectious diseases are developing resistance to common antibiotics. Common hospital germs, such as Escherichia coli and Klebsiella pneumoniae, have become resistant to most – and in some cases all, antibiotics currently available. What makes these bacteria so vulnerable is their extra outer membrane. Protects bacteria very well by preventing many substances from reaching the site of action. In particular, new drugs are missing to treat diseases caused by these gram-negative bacteria. An international research team involving researchers from Justus Liebig Giessen University (JLU) has now discovered a new peptide that attacks gram-negative bacteria at a previously unknown site of action.
Darobactin: A candidate for a new class of antibiotics
"It has not been possible to develop a new class of antibiotics against gram-negative bacteria since the 1960s, but that may be a candidate for it now," said Prof. Dr. Honey. Till Schäberle of the JLU Institute for Insect Biotechnology and project leader at the German Center for Infection Research (DZIF), whose working group is involved in the discovery. Scientists have used screening, a classic approach to natural matter research. Tim prof. Dr. Kim Kim Lewis of Northeastern University, Boston, Massachusetts (USA) tested bacterial symbiont extracts of entomopathogenic earthworms for activity against E. coli. The researchers were able to isolate a peptide they called "darobactin".
Darobactin consists of seven amino acids and exhibits structural peculiarities. Thus several amino acids are linked by unusual ring closures. The substance has no cellular toxicity – a prerequisite for use as an antibiotic. "We have already gained insight into how bacteria synthesize this molecule," says Prof. Schaber. "We are now working in the area of natural products research at JLU Insect Biotechnology Institute to increase production of this substance and create analogues."
Scientists have also determined the site of action of darobactin. They found that darobactin binds to the BamA protein found in the outer membrane of gram-negative bacteria. As a result, the structure of the functional outer membrane is disrupted and the bacteria die. "It is especially interesting that this unknown point of attack is located externally and that substances can easily reach it," explains Prof. Schaber.
Darobactin has shown excellent activity in infections with antibiotic-resistant Pseudomonas aeruginosa strains, Escherichia coli strains and Klebsiella pneumoniae strains. This makes darobactin a promising leader for the development of new antibiotics, and the urgency of this is demonstrated by the fact that the World Health Organization (WHO) has identified the research and development needs of resistant pathogens as a top priority for human health.
Researchers from the United States (Northeastern University, Boston, Massachusetts, Purdue University, West Lafayette, Indiana, J. Craig Venter Institute, La Jolla, California), from Germany (Justus, USA), participated in the paper published in the journal Nature. Liebig Giessen University, German Center for DZIF Infection Research, Giessen-Marburg-Langen Site, EMBL European Laboratory for Molecular Biology, Heidelberg) and Switzerland (University of Basel).
Original issues: Publication: Imai, Y., Meyer, K. J., Iinishi, A. et al. New antibiotic kills gram-negative pathogens. Nature (2019), DOI: 10.1038 / s41586-019-1791-1
Source: Justus Liebig Giessen University