Journal of Antimicrobial Chemotherapy, May 1, 2001
Cationic cholic acid derivatives displayed potent and broad-spectrum activity against multidrug-r... more Cationic cholic acid derivatives displayed potent and broad-spectrum activity against multidrug-resistant Gram-negative and-positive bacteria. Specific examples were effective permeabilizers of the outer membranes of many strains of multidrug-resistant Gram-negative bacteria and sensitized these to hydrophobic antibiotics. We also prepared a new cholic acid derivative with improved apparent selectivity for prokaryote membranes.
Compounds in a series of cholic acid derivatives, designed to mimic the activities of polymyxin B... more Compounds in a series of cholic acid derivatives, designed to mimic the activities of polymyxin B and its derivatives, act as both potent antibiotics and effective permeabilizers of the outer membranes of gram-negative bacteria. Some of these compounds rival polymyxin B in antibacterial activity against gram-negative bacteria and are also very active against gram-positive organisms. Other compounds interact synergistically with hydrophobic antibiotics to inhibit bacterial growth.
The antibacterial activities of cationic steroid antibiotics and cationic peptide antibiotics hav... more The antibacterial activities of cationic steroid antibiotics and cationic peptide antibiotics have been compared. Depolarization of bacterial membranes, activation of bacterial stress-related gene promoters, and changes in bacterial morphologies caused by these antibiotics suggest that cationic steroid and peptide antibiotics share mechanistic aspects. Modified cationic steroid antibiotics display improved selectivity for prokaryotic cells over eukaryotic cells presumably due to increased charge recognition.
Cationic steroid antibiotics have been developed that display broad-spectrum antibacterial activi... more Cationic steroid antibiotics have been developed that display broad-spectrum antibacterial activity. These compounds are comprised of steroids appended with amine groups arranged to yield facially amphiphilic morphology. Examples of these antibiotics are highly bactericidal, while related compounds effectively permeabilize the outer membranes of Gram-negative bacteria sensitizing these organisms to hydrophobic antibiotics. Cationic steroid antibiotics exhibit various levels of eukaryote vs. prokaryote cell selectivity, and cell selectivity can be increased via charge recognition of prokaryotic cells. Studies of the mechanism of action of these antibiotics suggest that they share mechanistic aspects with cationic peptide antibiotics.
Attachment of amino acids to cholic acid derivatives yielded compounds that sensitize Gramnegativ... more Attachment of amino acids to cholic acid derivatives yielded compounds that sensitize Gramnegative bacteria to hydropbobic antibiotics. Incorporation of three amino acid onto a cholic acid derivative via ester bonds was only achieved with non-a-branched amino acids. Three non-a-branched or three a-branched amino acids were coupled to the steroid backbone via amide bonds.
Mimics of squalamine and polymyxin B (PMB) have been prepared from cholic acid in hope of finding... more Mimics of squalamine and polymyxin B (PMB) have been prepared from cholic acid in hope of finding new antimicrobial agents. The squalamine mimics include the polyamine and sulphate functionalities found in the parent antibiotic, however, the positions relative to the steroid nucleus have been exchanged. The PMB mimics include the conservation of functionality among the polymyxin family of antibiotics, the primary amine groups and a hydrophobic chain. Although the squalamine and PMB mimics are morphologically dissimilar, they display similar activities. Both are simple to prepare and demonstrate broad spectrum antimicrobial activity against Gram-negative and Gram-positive organisms. Specific examples may be inactive alone, yet effectively permeabilise the outer membranes of Gram-negative bacteria rendering them sensitive to hydrophobic antibiotics. Problems associated with some of the squalamine and PMB mimics stem from their haemolytic activity and interactions with serum proteins, however, examples exist without these side effects which can sensitise Gram-negative bacteria to hydrophobic antibiotics.
[reaction: see text] Novel cholic acid-derived antimicrobial agents that decompose under mildly b... more [reaction: see text] Novel cholic acid-derived antimicrobial agents that decompose under mildly basic conditions have been prepared. These compounds range in biological properties from potent antibacterial activity to effective permeabilization of the outer membranes of Gram-negative bacteria.
We have prepared a triamine derivative of cholic acid with protecting groups on the amines that a... more We have prepared a triamine derivative of cholic acid with protecting groups on the amines that allow sequential amide formation. The triamine was formed from 3 alpha,7 alpha, 12 alpha-trihydroxycholan-24-ol with good stereoselectivity. Sequential removal of the amine protecting groups and amide formation was achieved in high-yielding steps and was performed in solution and on a solid support.
Alpha-galactosylceramides are potent stimulators of human T cells. Stimulation occurs through bin... more Alpha-galactosylceramides are potent stimulators of human T cells. Stimulation occurs through binding of the glycolipids by CD1d, presentation to T cells, and formation of a CD1d-glycolipid-T cell receptor complex. To facilitate the elucidation of the structural features of glycolipids necessary for T cell stimulation, alpha-galactosylceramides have been prepared with small molecules appended at the C6 position of the sugar. The appended molecules do not significantly influence the abilities of the glycolipids to stimulate T cells. [reaction: see text]
Cholic acid derivatives appended with amine groups have been prepared for use as permeabilizers o... more Cholic acid derivatives appended with amine groups have been prepared for use as permeabilizers of the outer membranes of Gram-negative bacteria. These compounds interact synergistically with antibiotics such as erythromycin and novobiocin to inhibit growth of Gram-negative bacteria. When a hydrophobic chain is included on the permeabilizers, they can be converted into potent antibiotics. The role of the hydrophobic chain is to facilitate self-promoted transport of the cholic acid derivatives across the outer membrane of Gramnegative bacteria. These compounds share activities found with polymyxin B and derivatives.
Journal of Antimicrobial Chemotherapy, May 1, 2001
Cationic cholic acid derivatives displayed potent and broad-spectrum activity against multidrug-r... more Cationic cholic acid derivatives displayed potent and broad-spectrum activity against multidrug-resistant Gram-negative and-positive bacteria. Specific examples were effective permeabilizers of the outer membranes of many strains of multidrug-resistant Gram-negative bacteria and sensitized these to hydrophobic antibiotics. We also prepared a new cholic acid derivative with improved apparent selectivity for prokaryote membranes.
Compounds in a series of cholic acid derivatives, designed to mimic the activities of polymyxin B... more Compounds in a series of cholic acid derivatives, designed to mimic the activities of polymyxin B and its derivatives, act as both potent antibiotics and effective permeabilizers of the outer membranes of gram-negative bacteria. Some of these compounds rival polymyxin B in antibacterial activity against gram-negative bacteria and are also very active against gram-positive organisms. Other compounds interact synergistically with hydrophobic antibiotics to inhibit bacterial growth.
The antibacterial activities of cationic steroid antibiotics and cationic peptide antibiotics hav... more The antibacterial activities of cationic steroid antibiotics and cationic peptide antibiotics have been compared. Depolarization of bacterial membranes, activation of bacterial stress-related gene promoters, and changes in bacterial morphologies caused by these antibiotics suggest that cationic steroid and peptide antibiotics share mechanistic aspects. Modified cationic steroid antibiotics display improved selectivity for prokaryotic cells over eukaryotic cells presumably due to increased charge recognition.
Cationic steroid antibiotics have been developed that display broad-spectrum antibacterial activi... more Cationic steroid antibiotics have been developed that display broad-spectrum antibacterial activity. These compounds are comprised of steroids appended with amine groups arranged to yield facially amphiphilic morphology. Examples of these antibiotics are highly bactericidal, while related compounds effectively permeabilize the outer membranes of Gram-negative bacteria sensitizing these organisms to hydrophobic antibiotics. Cationic steroid antibiotics exhibit various levels of eukaryote vs. prokaryote cell selectivity, and cell selectivity can be increased via charge recognition of prokaryotic cells. Studies of the mechanism of action of these antibiotics suggest that they share mechanistic aspects with cationic peptide antibiotics.
Attachment of amino acids to cholic acid derivatives yielded compounds that sensitize Gramnegativ... more Attachment of amino acids to cholic acid derivatives yielded compounds that sensitize Gramnegative bacteria to hydropbobic antibiotics. Incorporation of three amino acid onto a cholic acid derivative via ester bonds was only achieved with non-a-branched amino acids. Three non-a-branched or three a-branched amino acids were coupled to the steroid backbone via amide bonds.
Mimics of squalamine and polymyxin B (PMB) have been prepared from cholic acid in hope of finding... more Mimics of squalamine and polymyxin B (PMB) have been prepared from cholic acid in hope of finding new antimicrobial agents. The squalamine mimics include the polyamine and sulphate functionalities found in the parent antibiotic, however, the positions relative to the steroid nucleus have been exchanged. The PMB mimics include the conservation of functionality among the polymyxin family of antibiotics, the primary amine groups and a hydrophobic chain. Although the squalamine and PMB mimics are morphologically dissimilar, they display similar activities. Both are simple to prepare and demonstrate broad spectrum antimicrobial activity against Gram-negative and Gram-positive organisms. Specific examples may be inactive alone, yet effectively permeabilise the outer membranes of Gram-negative bacteria rendering them sensitive to hydrophobic antibiotics. Problems associated with some of the squalamine and PMB mimics stem from their haemolytic activity and interactions with serum proteins, however, examples exist without these side effects which can sensitise Gram-negative bacteria to hydrophobic antibiotics.
[reaction: see text] Novel cholic acid-derived antimicrobial agents that decompose under mildly b... more [reaction: see text] Novel cholic acid-derived antimicrobial agents that decompose under mildly basic conditions have been prepared. These compounds range in biological properties from potent antibacterial activity to effective permeabilization of the outer membranes of Gram-negative bacteria.
We have prepared a triamine derivative of cholic acid with protecting groups on the amines that a... more We have prepared a triamine derivative of cholic acid with protecting groups on the amines that allow sequential amide formation. The triamine was formed from 3 alpha,7 alpha, 12 alpha-trihydroxycholan-24-ol with good stereoselectivity. Sequential removal of the amine protecting groups and amide formation was achieved in high-yielding steps and was performed in solution and on a solid support.
Alpha-galactosylceramides are potent stimulators of human T cells. Stimulation occurs through bin... more Alpha-galactosylceramides are potent stimulators of human T cells. Stimulation occurs through binding of the glycolipids by CD1d, presentation to T cells, and formation of a CD1d-glycolipid-T cell receptor complex. To facilitate the elucidation of the structural features of glycolipids necessary for T cell stimulation, alpha-galactosylceramides have been prepared with small molecules appended at the C6 position of the sugar. The appended molecules do not significantly influence the abilities of the glycolipids to stimulate T cells. [reaction: see text]
Cholic acid derivatives appended with amine groups have been prepared for use as permeabilizers o... more Cholic acid derivatives appended with amine groups have been prepared for use as permeabilizers of the outer membranes of Gram-negative bacteria. These compounds interact synergistically with antibiotics such as erythromycin and novobiocin to inhibit growth of Gram-negative bacteria. When a hydrophobic chain is included on the permeabilizers, they can be converted into potent antibiotics. The role of the hydrophobic chain is to facilitate self-promoted transport of the cholic acid derivatives across the outer membrane of Gramnegative bacteria. These compounds share activities found with polymyxin B and derivatives.
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