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Mode of action of the 4th generation of antibacterial compounds lipophosphonoxins
Helusová, Michaela ; Mikušová, Gabriela (advisor) ; Mašín, Jiří (referee)
Lipophosphonoxins are small synthetic antimicrobials targeting the cytoplasmic membrane of bacteria. This thesis focuses on comparison of three lipophosphonoxins which differ in the number of carbons in its modules and in antimicrobial and hemolytic activity. The most promising candidate compound is lipophosphonoxin 7072 showing good antimicrobial activity as well as low hemolytic activity. Other two tested lipophosphonoxins are 7070 displaying high hemolytic activity and weakly antibacterial lipophosphonoxin 7107. The pore-forming activity of lipophosphonoxins is investigated using model membranes as well as living bacteria Staphylococcus aureus and Escherichia coli. The results show that small difference in structure can fundamentally affect the activity of these molecules. Lipophosphonoxins 7072 a 7070 display equal antibacterial activity against tested bacteria by forming pores in the bacterial membrane. Bacteria rapidly die of loss of membrane potential caused by lipophosphonoxins. The high hemolytic activity of the compound 7070 is probably related with its preference for uncharged membranes. The weak antimicrobial activity of 7107 is caused by its capability to form only small pores and its incapability to overcome and disrupt the outer membrane. Key words: antimicrobial agents,...
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Mode of action of the 4th generation of antibacterial compounds lipophosphonoxins
Helusová, Michaela ; Mikušová, Gabriela (advisor) ; Mašín, Jiří (referee)
Lipophosphonoxins are small synthetic antimicrobials targeting the cytoplasmic membrane of bacteria. This thesis focuses on comparison of three lipophosphonoxins which differ in the number of carbons in its modules and in antimicrobial and hemolytic activity. The most promising candidate compound is lipophosphonoxin 7072 showing good antimicrobial activity as well as low hemolytic activity. Other two tested lipophosphonoxins are 7070 displaying high hemolytic activity and weakly antibacterial lipophosphonoxin 7107. The pore-forming activity of lipophosphonoxins is investigated using model membranes as well as living bacteria Staphylococcus aureus and Escherichia coli. The results show that small difference in structure can fundamentally affect the activity of these molecules. Lipophosphonoxins 7072 a 7070 display equal antibacterial activity against tested bacteria by forming pores in the bacterial membrane. Bacteria rapidly die of loss of membrane potential caused by lipophosphonoxins. The high hemolytic activity of the compound 7070 is probably related with its preference for uncharged membranes. The weak antimicrobial activity of 7107 is caused by its capability to form only small pores and its incapability to overcome and disrupt the outer membrane. Key words: antimicrobial agents,...
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Mode of daptomycin action and mechanism of resistance
Helusová, Michaela ; Mikušová, Gabriela (advisor) ; Lichá, Irena (referee)
Daptomycin is one of antimicrobial peptides. These molecules are part of immune system of all organisms. Daptomycin consists of a cyclic peptide core and a lipophilic tail. Daptomycin is produced by Streptomyces roseosporus and is used to treat serious gram-positive infections. Daptomycin is active also against methicillin-resistant Staphylococcus aureus. Its antimicrobial effect depends on the presence of calcium ions and phosphatidylglycerol. Daptomycin targets bacterial cytoplasmic membrane, where it forms oligomers. Mode of action of daptomycin probably includes pore-forming effect leading to membrane damage. This disturbance causes ion efflux from cytoplasm which leads to membrane potential disruption, which results in inhibition of macromolecular synthesis and cell death. Daptomycin also causes changes in cell morphology. Despite its unusual mode of action, several mechanisms of resistance have emerged in some pathogenic strains. These are for example decrease in the amount of phosphatidylglycerol in the membrane, increase in the amount of lysylphosphatidylglycerol, release of membrane phospholipids or mutations in genes which control peptidoglycan synthesis.
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