Researchers at Karolinska Institutet, Umeå University and University of Bonn have identified a new group of molecules that have antibacterial effects against many antibiotic-resistant bacteria. Since the properties of molecules can easily be chemically altered, the hope is that you will be able to develop new, effective antibiotics with few side effects. The results were published in the scientific journal PNAS.
The world’s growing antibiotic resistance is alarming, while a few new types of antibiotics have been developed in the past 50 years. So there is a great need to find new antibacterial materials.
The majority of antibiotics used clinically work by inhibiting the ability of bacteria to form their protective cell wall, causing the bacteria to rupture (lys). The well-known antibiotic penicillin inhibits the enzymes that build the cell wall. Newer antibiotics such as daptomycin or the newly discovered teixobactin bind to a special molecule, the second lipid, which all bacteria need to build the cell wall. The antibiotics that bind to this building block of the cell wall are usually very large and complex molecules, and therefore difficult to improve by chemical methods. In addition, they are usually inactive against certain problem-causing bacteria and are surrounded by an outer cell membrane, which prevents the penetration of these antibacterial substances.
– Lipid II is a very attractive target for new antibiotics. We’ve identified the first small antibacterial that works by binding to this lipid molecule, and in our study we didn’t find any resistant bacterial mutants, which is very promising, says Birgitta Henrik Normark, a professor in the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and one of the authors. The three correspond to the article.
In the new study, researchers at Karolinska Institutet and Umeå University tested a large number of chemicals for their ability to break down bacteria of the pneumococcus type, the most common cause of community-acquired pneumonia. Preliminary tests were conducted in collaboration with the Consortium for Chemical Biology of Sweden (CBCS), a national research infrastructure at SciLifeLab. The researchers found after careful observation of the active substances of this examination In cooperation with the University of Bonn in Germany, that a group of molecules called THCz It inhibits bacterial cell wall formation by binding to lipid II. The molecules can also prevent the sugar capsule formation that pneumococci need to escape the immune system and cause disease.
– The advantage of small molecules like these is that they are easy to change chemically. We hope to be able to alter THCz so that the antibacterial effect is increased and any negative effects on human cells decreased, says Frederic Almqvist, a professor in the Umea University Department of Chemistry and one of the corresponding authors.
In laboratory experiments, THCz has been shown to have antibacterial effects against many antibiotic-resistant bacteria, such as methicillin-resistant staphylococcus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant pneumococci (PNSP). An antibacterial effect has also been found against gonococcus that causes gonorrhea, and the Mycobacterium tuberculosis that can cause severe disease such as tuberculosis in humans. The researchers were unable to identify any bacteria that developed resistance to THCz in the laboratory environment.
– Now we will also start experimenting To change the THCz molecule so that it can penetrate the outer cell membrane found in some bacteria, especially the multi-resistant bacteria that are difficult to treat, says Tanya Schneider, a professor at the Institute of Pharmaceutical Microbiology at the University of Bonn and one of the corresponding authors.
The research was carried out in close collaboration with Karolinska University Hospital and University Hospital Bonn. The study was funded by the Foundation for Strategic Research, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Stockholm District, Göran Gustafsson Foundation, Deutsche Forschungsgemeinschaft (DFG) and Deutschen Zentrum für Infektionsforschung (DZIF). No conflict of interest has been reported.
the post: “THCz – small molecules with antimicrobial activity that inhibits cell wall lipid intermediates”. Elisabeth Rethobber, Torbjorn Wixe, Kevin C. Ludwig, Anna Muller, Hannah Ofel, Fabian Green, Anders E. G. Lindgrenb, Sandra Muschiol, Priyanka Nanabannini, Anna Erickson, Tanya Schneider, Staffan Normark, Birgitta Henrix Normext, Peter Almarquist, Frederic Normark. PNAS (Proceedings of the National Academy of Sciences), online November 16, 2021, doi:10.1073/pnas.2108244118.
For more information please contact:
Birgitta Henrik Normark, Professor
Department of Microbiology, Oncology and Cell Biology, Karolinska Institutet
the phone: +46 (0) 851771216
Car: +46 (0) 70678 0317
email: [email protected]
Frederic Almqvist, Professor
Department of Chemistry, Umeå University
Tel: +46 (0) 90786 6925
Car: +46 (0) 70397 9097
email: [email protected]
Tania Schneider, Professor
Institute of Pharmaceutical Microbiology, University of Bonn, Germany
Tel: +49 (0) 228 735 688
email: [email protected]
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