From: Karolinska Institutet KI News
November 17, 2021 -- Researchers at
Karolinska Institutet, Umeå University, and the University of Bonn have
identified a new group of molecules that have an antibacterial effect against
many antibiotic-resistant bacteria. Since the properties of the molecules can
easily be altered chemically, the hope is to develop new, effective antibiotics
with few side effects. The findings have been published in the scientific
journal PNAS.
The increasing resistance to antibiotics
in the world is alarming while few new types of antibiotics have been developed
in the past 50 years. There is therefore a great need to find new antibacterial
substances.
The majority of antibiotics in clinical
use work by inhibiting the bacteria’s ability to form a protective cell wall,
causing the bacteria to crack (cell lysis). Besides the well-known penicillin,
that inhibit enzymes building up the wall, newer antibiotics such as daptomycin
or the recently discovered teixobactin bind to a special molecule, lipid II.
Lipid II is needed by all bacteria to build up the cell wall. Antibiotics that
bind to this cell wall building block are usually very large and complex
molecules and therefore more difficult to improve with chemical methods. These
molecules are in addition mostly inactive against a group of problematic
bacteria, which are surrounded by an additional layer, the outer membrane, that
hinders penetration of these antibacterials.
Attractive target for new antibiotics
“Lipid II is a very attractive target
for new antibiotics. We have identified the first small antibacterial compounds
that work by binding to this lipid molecule, and in our study, we found no
resistant bacterial mutants, which is very promising,” says Birgitta Henriques Normark,
professor at the Department
of Microbiology, Tumor and Cell Biology, Karolinska Institutet, and one of
the article’s three corresponding authors.
In this study, researchers at Karolinska
Institutet and Umeå University in Sweden have tested a large number of chemical
compounds for their ability to lyse pneumococci, bacteria that are the most
common cause of community-acquired pneumonia. The initial tests were carried
out in collaboration with the Chemical Biology Consortium Sweden (CBCS), a
national research infrastructure at SciLifeLab. After a careful follow-up of
active compounds from this screening, the researchers, in collaboration with
the University of Bonn in Germany, found that a group of molecules called THCz
inhibits the formation of the cell wall of the bacterium by binding to lipid
II. The molecules could also prevent the formation of the sugar capsule that
pneumococci need to escape the immune system and to cause disease.
Easier to change chemically
“The advantage of small molecules like
these is that they are easier to change chemically. We hope to be able to
change THCz so that the antibacterial effect increases and any negative effects
on human cells decrease,” says Fredrik Almqvist, professor at the Department of
Chemistry at Umeå 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). An antibacterial effect was
also found against gonococci, which causes gonorrhoea, and mycobacteria,
bacteria that can cause severe diseases such as tuberculosis in humans. The
researchers were unable to identify any bacteria that developed resistance to
THCz in a laboratory environment.
Penetrate the outer cell membrane
We will now also initiate attempts to
change the THCz molecule, allowing it to penetrate the outer cell membrane
found in some, especially intractable, multi-resistant bacteria,” says Tanja
Schneider, 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 the University Hospital
in Bonn. The study was funded by the Swedish Foundation for Strategic Research,
the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Region
Stockholm, the Göran Gustafsson Foundation, the German Research Foundation
(DFG; TRR261) and the German Center for Infection Research (DZIF). There are no
reported conflicts of interest.
Publication
”THCz - Small
molecules with antimicrobial activity that block cell wall lipid intermediates”.
Elisabeth Reithuber, Torbjörn Wixe, Kevin C. Ludwig, Anna Müller, Hanna Uvell,
Fabian Grein, Anders E.G. Lindgrenb, Sandra Muschiol, Priyanka Nannapaneni,
Anna Eriksson, Tanja Schneider, Staffan Normark, Birgitta Henriques-Normark,
Fredrik Almqvist, Peter Mellroth. PNAS (Proceedings of the
National Academy of Sciences), online 16 November 2021, doi:
10.1073/pnas.2108244118.
https://news.ki.se/new-group-of-antibacterial-molecules-identified
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