2024-03-18 23:04:06
19.03.2024
New antimicrobial strategies are urgently needed to contain pathogens. This is particularly true for Gram-negative bacteria, which are protected from attack by antibiotics by a thick second membrane.
Microbiologists from the Faculty of Biology and Biotechnology at the Ruhr University Bochum have compared the effects of five different substances that inhibit the formation of this outer membrane. In addition to the expected consequences, they found – depending on the substance – a number of additional cellular responses of the bacterial cell.
The results can help to better assess the application potential of such inhibitors and were published on March 6, 2024 in the Journal of Biological Chemistry.
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 coloring behavior. Gram-negative pathogens pose 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 produce this outer membrane are unique and are therefore interesting targets for specific antibiotics against this group of bacteria,” explains Prof. Dr. Franz Narberhaus, holder of the Chair of Biology of Microorganisms and leader of the study.
Key enzyme can be inhibited
A particularly attractive target for antibiotic development is the enzyme LpxC, 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 reacts to blocking 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 an accumulation of inactive LpxC in the bacterial cells. In addition, the bacteria were killed by all five substances, although with significantly different efficiencies.
Equal and yet not equal
Although all inhibitors target the same site, there were a number of substance-specific differences in the bacterial response to treatment. Four of the substances changed the balance in membrane composition, a sign of acute membrane stress. Some substances induced a general stress response or interfered with metabolic pathways that are not directly related to membrane biosynthesis.
“We learn from this that you should look closely at what is happening in the bacteria before using such substances,” warns Prof. Dr. Julia Bandow, head of the Center for Systems-Based Antibiotic Research CESAR, where some of the studies were carried out. Even if the same enzyme is inhibited, this does not automatically mean that the bacteria’s cellular responses are identical.
New antimicrobial agents with great potential
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, which combats bacterial infections very efficiently and is free of side effects, at least in animal models.
“We are now very interested in testing how bacteria react to this substance,” says Franz Narberhaus. In the future, the bacterial response to other active substances that attack earlier or later steps in the biosynthesis of the outer membrane will also be investigated. Despite the great potential of such antibiotics, little is known about their mechanism of action and the bacterial reaction to them.
» Originalpublikation
Source: University of Bochum
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