19.03.2024
New antimicrobial strategies are urgently needed to control pathogens. This is especially true for Gram-negative bacteria, which are protected from antibiotic attack by a thick second membrane.
Microbiologists from the Faculty of Biology and Biotechnology at the Ruhr University compared the effects of five different substances that inhibit the formation of this outer membrane. In addition to the expected effects, they discovered – depending on the material – several additional cellular responses in the bacterial cell.
The results help to better assess the applicability of such inhibitors and were published in the journal Biological Chemistry on March 6, 2024.
The outer membrane of Gram-negative bacteria as a target for antibiotics
For more than a hundred years, bacteria have been classified into Gram-positive and Gram-negative bacteria based on their staining behavior. Gram-negative pathogens present a particular challenge because they are surrounded by a second membrane that does not allow many antibiotics to pass through.
“On the other hand, the enzymes that make up this outer membrane are unique and therefore interesting targets for specific antibiotics against these bacteria,” says Prof. Dr. Franz Narberhaus, Chair of Microbial Biology and head of the study.
A key enzyme may be inhibited
A particularly attractive target for antibiotic development is the LpxC enzyme, which catalyzes the first irreversible step in the biosynthesis of the outer membrane of Gram-negative bacteria. To find out how the model bacterium Escherichia coli works to inhibit this enzyme, the researchers compared the cellular response to five different LPXC inhibitors. All five substances were able to bind to LpxC and inhibit this enzyme, leading to the accumulation of inactive LpxC in bacterial cells. In addition, bacteria were killed by all five substances, although with significantly different efficacy.
Equal but not equal
Although all inhibitors targeted the same site, there were many subject-specific differences in bacterial response to treatment. Four substances altered the equilibrium in membrane composition, an indication of acute membrane stress. Some substances induce a general stress response or interfere with metabolic pathways not directly related to membrane biogenesis.
“We learn from this that you have to look closely at what's going on in the bacteria before using such materials,” said Professor Dr. Julia Panto is head of systems-based antibiotic research at CESAR, where some of the research was carried out. Even if the same enzyme is inhibited, this does not automatically mean that the bacterial cellular responses are the same.
New antimicrobial agents with superior potency
Unfortunately, all currently available LpxC inhibitors are unsuitable for clinical use due to side effects in humans and animals. However, there is hope in a new LpxC inhibitor described a few months ago that fights bacterial infections more efficiently and is free of side effects, at least in animal models.
“We are now very interested in testing how bacteria react to this material,” says Franz Nürburghaus. In the future, the bacterial response to other active substances that attack earlier or later steps in outer membrane biosynthesis will also be investigated. Despite the great potential of such antibiotics, little is known about their mechanism of action and bacterial response to them.
» Original publication
They are: University of Bochum