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Mode of action and nature of different susceptibility of bacteria to antibacterial compounds lipophosphonoxins
Havlová, Noemi ; Mikušová, Gabriela (advisor) ; Krásný, Libor (referee)
Lipophosphonoxins (LPPO) are small synthetic antibacterial compounds targeting the cytoplasmic membrane. 1st generation of LPPO (LPPO I) displays an antimicrobial activity against Gram positive bacteria, however they do not show any activity against Gram negatives. After the modification of the iminosugar module (bearing the positive charge) the 2nd generation of LPPO (LPPO II) were synthetized. LPPO II exhibit broadened activity against Gram positive bacteria and also kill Gram negatives, including multiresistant strains. This work focuses on the mode of action of LPPO - the pore-forming activity of these substances is investigated on model membranes as well as in vivo. It also deals with the nature of different activity against Gram positive and Gram negative bacteria using model bacteria Bacillus subtilis and Escherichia coli. The results show that the insensitivity of Gram negative bacteria against LPPO I is probably caused by the different cell wall structure and the presence of the outer membrane that LPPO are almost unable to overcome. Also, the composition of phospholipids in the target membrane influences the antimicrobial activity of LPPO. Higher proportion of phospholipids with neutral charge reduces the LPPO pore-forming activity but is also responsible for low cytotoxicity in...
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Mode of action and nature of different susceptibility of bacteria to antibacterial compounds lipophosphonoxins
Havlová, Noemi ; Seydlová, Gabriela (advisor) ; Krásný, Libor (referee)
Lipophosphonoxins (LPPO) are small synthetic antibacterial compounds targeting the cytoplasmic membrane. 1st generation of LPPO (LPPO I) displays an antimicrobial activity against Gram positive bacteria, however they do not show any activity against Gram negatives. After the modification of the iminosugar module (bearing the positive charge) the 2nd generation of LPPO (LPPO II) were synthetized. LPPO II exhibit broadened activity against Gram positive bacteria and also kill Gram negatives, including multiresistant strains. This work focuses on the mode of action of LPPO - the pore-forming activity of these substances is investigated on model membranes as well as in vivo. It also deals with the nature of different activity against Gram positive and Gram negative bacteria using model bacteria Bacillus subtilis and Escherichia coli. The results show that the insensitivity of Gram negative bacteria against LPPO I is probably caused by the different cell wall structure and the presence of the outer membrane that LPPO are almost unable to overcome. Also, the composition of phospholipids in the target membrane influences the antimicrobial activity of LPPO. Higher proportion of phospholipids with neutral charge reduces the LPPO pore-forming activity but is also responsible for low cytotoxicity in...
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Role of cytoplasmic membrane and cell wall in bacterial resistance to cationic antimicrobial peptides
Havlová, Noemi ; Seydlová, Gabriela (advisor) ; Vopálenská, Irena (referee)
Cationic antimicrobial peptides are part of the innate immune system of all organisms. Their properties such as structure, charge, amphipathicity and hydrophobicity make them promising agents with the potential for use not only in treatment of bacterial infections but also against some viruses, parasites, fungi and cancer cells. One of their possible targets is the cytoplasmic membrane, which they permeabilize. This mode of action has several advantages. The important feature of antimicrobial peptides is their selectivity for bacterial membranes, which makes them harmless to eukaryotic host cells. Another advantage is that the development of bacterial resistance against these peptides is more difficult since the action of antimicrobial peptides is rapid. Nevertheless, there appeared some bacterial strains that are insensitive to already used antimicrobial peptides. By using target modification resistant bacteria are able to prevent the bactericidal effects of the antimicrobial peptides. At the level of cytoplasmic membrane bacteria can alter its electrostatic or structural properties of membrane lipids and thus the antimicrobial peptides lose their ability to interact with the membrane and permeabilize it. Understanding the mode of action of antimicrobial peptides and mechanisms by which bacteria...
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