Researchers from Umea University, Karolinska Institutet and the University of Bonn discovered a new class of molecules that have antibacterial properties against many antibiotic-resistant bacteria. The properties of these molecules can be easily changed chemically. This allows them to create new effective antibiotics that have no adverse effects. These results were published in the scientific journal PNAS.
The increasing resistance of the world to antibiotics is alarming, despite the fact that only a handful of new antibiotics were developed over the last 50 years. There is therefore a great need for new antibacterial compounds.
The majority of antibiotics that are in clinical use are able to inhibit the ability of bacteria to build the cell wall that protects itself, causing the bacteria to break through (cell lysis). Besides the well-known penicillin, that blocks enzymes responsible for building the wall, newer antibiotics like daptomycin or the newly discovered teixobactin can bind to a particular molecules, lipid II. Lipid II is required by all bacteria to build the cell wall. Antibiotics that are able to bind to this building block are typically large and complex molecules , and therefore , more difficult to improve using chemical methods. These molecules are also inactive against a number of harmful bacteria. The outer membrane surrounds these molecules and blocks them from being absorbed.
Lipid II is a very appealing target for the development of new antibiotics. We have identified the first antibacterial compounds that work by binding to this lipid molecule, and in our study, we found no resistant bacterial mutants which is very promising.”
Birgitta Normark, Professor, Department of Microbiology, Tumor and Cell Biology, Karolinska Institut and one of the three corresponding authors of the article
In this study, researchers at Karolinska Institutet and Umea University in Sweden have tested a large number of chemical compounds for their ability to kill pneumococci, bacteria that are the most common cause of community-acquired pneumonia. The Chemical Biology Consortium Sweden (CBCS) is a national infrastructure for research at SciLifeLab was the first to conduct the tests. Researchers working in conjunction with the University of Bonn, Germany, discovered that THCz is a class of molecules, blocks the creation of cell walls through binding to lipid II. These molecules could also prevent the formation of the sugar capsule, which is required by pneumococci to escape the immune system.
“The benefit of small molecules like these is that they are easily to alter chemically. We hope to be able to alter THCz to make sure that the antibacterial effect is increased and negative effects on human cells diminish,” says Fredrik Almqvist, professor at the Department of Chemistry at Umea University and one of the corresponding authors.
In laboratory experiments, THCz have an antibacterial effect against many antibiotic-resistant bacteria, such as methicillin-resistant staphylococci (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant pneumococci (PNSP). The antibacterial effect was also observed against gonococci which causes gonorrhoea, and mycobacteria bacteria that could cause severe diseases such as tuberculosis in humans. The researchers were not able to identify any bacteria that developed resistance to THCz in a laboratory.
“We will also begin attempts to alter the THCz THCzmolecule, allowing it to enter the cell’s outer membrane found in some particularly intractable multi-resistant bacteria” says Tanja Schneider, a professor at the Institute of Pharmaceutical Microbiology at the University of Bonn and one of the authors.
and. al. (2021). THCz – Small molecules which have antimicrobial activity and block the cell wall lipid intermediaries. PNAS. doi.org/10.1073/pnas.2108244118.
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