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.
The researchers say - "Considering the alarming emergence of resistance to most antibiotics and the need for new antibiotics, the finding here of a small-molecule class, THCz, that displayed bactericidal activity against gram-positive and selected gram-negative bacteria, is of the greatest importance. We found that THCz target the cell envelope synthesis and can easily be synthesized and modified, and resistance did not readily develop in vitro. Thus, THCz are promising scaffolds for development of bacterial cell wall inhibitors."
Since the discovery of Penicillin by Sir Alexander Fleming in 1928, mankind has depended much on antibiotics. But the increasing resistance to antibiotics 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.
Most of the antibiotics work by inhibiting the growth of the protective bacterial cell wall. This causes the bacteria to crack (cell lysis). But the newer classes of antibiotics like Daptomycin and Teixobactin bind to a special molecule, lipid II.
Lipid II is a disaccharide pentapeptide peptidoglycan subunit linked to an undecaprenyl lipid vehicle (C55 -P) via a pyrophosphate group. It is synthesized in the cytoplasm and flipped over to the outer leaflet of the plasma membrane to provide cell wall building blocks for PBPs (Penicillin Binding Proteins)
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.
This newly found, 1-amino substituted tetrahydrocarbazole (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.
Prof Fredrik Almqvist, at the Department of Chemistry at Umeå University states - "The advantage of small molecules like these is that they are more easy 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"
Prof Tanja Schneider, at the Institute of Pharmaceutical Microbiology at the University of Bonn says - "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"
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.
The researchers say - "Considering the alarming emergence of resistance to most antibiotics and the need for new antibiotics, the finding here of a small-molecule class, THCz, that displayed bactericidal activity against gram-positive and selected gram-negative bacteria, is of the greatest importance. We found that THCz target the cell envelope synthesis and can easily be synthesized and modified, and resistance did not readily develop in vitro. Thus, THCz are promising scaffolds for development of bacterial cell wall inhibitors."
Since the discovery of Penicillin by Sir Alexander Fleming in 1928, mankind has depended much on antibiotics. But the increasing resistance to antibiotics 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.
Most of the antibiotics work by inhibiting the growth of the protective bacterial cell wall. This causes the bacteria to crack (cell lysis). But the newer classes of antibiotics like Daptomycin and Teixobactin bind to a special molecule, lipid II.
Lipid II is a disaccharide pentapeptide peptidoglycan subunit linked to an undecaprenyl lipid vehicle (C55 -P) via a pyrophosphate group. It is synthesized in the cytoplasm and flipped over to the outer leaflet of the plasma membrane to provide cell wall building blocks for PBPs (Penicillin Binding Proteins)
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.
This newly found, 1-amino substituted tetrahydrocarbazole (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.
Prof Fredrik Almqvist, at the Department of Chemistry at Umeå University states - "The advantage of small molecules like these is that they are more easy 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"
Prof Tanja Schneider, at the Institute of Pharmaceutical Microbiology at the University of Bonn says - "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"
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.
