Polymyxin membrane interaction

Oxytetracycline hydrochloride is an antibiotic that inhibits bacterial protein synthesis. Polymyxin B interacts with phospholipid components of bacterial cell membrane, increasing cell wall permeability. It is indicated in the treatment of superficial ocular infections involving the conjunctiva and/or cornea caused by susceptible organisms. 

Raynor, R.L., Bin, Z., and Kuo, J.R, 1991, Membrane interaction of amphiphilic polypeptides mastopran, mellitin, polymyxin B, and cardiotoxin - diffrential inhibition of protein kinase C, Ca -calmodulin dependent protein kinase-II and synaptosomal membrane Na,K-ATPase and Na pump and differentiation of H 160 cells, J. Biol Chem. 266 2753-2758. 

A novel cyclic lipopeptide antibiotic was isolated from cultures of Strep-tomyces roseosporus grown in the presence of decanioc acid. Daptomycin interacts with the bacterial cell membrane and interferes with membrane potential.Unlike polymyxin B, daptomycin can target majority of clinically relevant Gram-positive pathogens. 

The polymyxins are polypeptide antibiotics that contain both hydrophilic and lipophilic regions. These antibiotics accumulate in the cell membrane and probably interact with membrane phospholipids. Most likely the fatty acid portion of the antibiotic penetrates the hydrophobic portion of the membrane phospholipid and the polypeptide ring binds to the exposed phosphate... 

Artificial asymmetric membranes composed of outer membranes of various species of Gram-negative bacteria and an inner leaflet of various phospholipids have been prepared using the Montal-Mueller technique [65]. Such planar bilayers have been used, for example, to study the molecular mechanism of polymyxin B-mem-brane interactions. A direct correlation between surface charge density and self-promoted transport has been found [66]. 

Microbes also have a plasma membrane that resides adjacent to their cell wall. Polymyxins are amphipathic agents (containing both nonpolar, lipophilic and polar, lipophobic groups) that interact with phospholipids in microbial cell membranes. The result is disruption of the membrane and increased permeability. However, because microbial and mammalian cell membranes are not exceedingly dissimilar, polymixins can produce significant toxicity in humans (i.e., they have low selective toxicity). This is also true for the related drug nystatin. This is why these particular antibiotics are not generally used systemically and are usually restricted to topical application. 

Chromosomal mutants of Ps. aeruginosa produced by stepwise exposure to the antibiotic polymyxin are resistant to this drug and to EDTA [175]. The mechanism of this resistance is related to a defective self-promoted uptake pathway in which the cells contain increased amounts of a major outer membrane protein (HI) with a corresponding decrease in envelope Mg2+ [175, 176]. Protein HI may replace Mg2+ at cross-bridging sites with LPS these sites are normally those at which interaction occurs with Mg2+, such as EDTA, or at which displacement of Mg2+ takes place, for example, polymyxin [177, 178],... 

The polymyxins are cationic, basic, and amphipathic poljtpeptides that interact with lipopolysaccharides in the outer membrane of bacilli. They potently neutralize endotoxin, reduce blood endotoxin concentrations in patients with septic shock during direct hemoperfusion over immobilized poljmyxin B fibers, and are bactericidal for many Gram-negative rods, even in resting bacteria. Alteration of the cell wall is also thought to be the mechanism of damage to renal epithelia and to the nervous system. 

Some antibacterial agents interact with the plasma membrane of bacterial cells to affect membrane permeability. This has fatal results for the cell. Polymyxins and tyrothricin operate in this way. 

Polymyxins are amphipathic agents that interact with phospholipids and disrupt the structure of cell membranes to increase permeability. Polymyxin B sensitivity apparently is related to the phospholipid content of the cell wall-membrane complex, which may prevent access of the drug to the cell membrane. 

Of several polymyxins isolated and investigated (A, B, C, D, E, and M) only compounds B and E are in veterinary use, both as sulfate salts. Polymyxin B is a mixture of Bi and B2. Of greater clinical use is polymyxin E, more commonly known as colistin, and used as colistin methanesulfonate. Their cationic structure accounts for their disruptive interaction with cell membrane phospholipids and has been described as a detergent-like action. Polymyxins, which are highly ionized molecules, are polar and very poorly lipid-soluble. 

The amino groups of the DAB residues in the cyclic polypeptide portion of the polymyxin molecule are necessary for the antimicrobial activity, which is reduced on acetylation [142]. Removal of the side chain from the molecule also reduces the activity by about 70% [143]. Various techniques have been used to probe the molecular interaction between polymyxin and the membrane components. Few [144] showed that polymyxin interacts with monolayers prepared from lipids and phospholipids of bacterial origin. Penetration of the mono-layers was followed by an increase in surface pressure, and polymyxin E was... 

The next barrier present in gram-negative bacteria is also a continuous, but a much more compact, layer of closely packed macromolecules. This entity, referred to as the outer membrane, consists predominantly of lipopolysaccharides (LPS), proteins, and phospholipids. The proteins have been estimated to contribute to about 50% of the surface area of this layer. The lipid-protein-polysaccharide components of the outer membrane form a matrix which appears in cross section as a typical double-tracked structure, similar to a phospholipid bilayer. This matrix is involved in a multiplicity of interactions of the cell surface with its exterior and interior environment. The outer membrane is known to function as a barrier to a large number of compounds, such as the antibiotics, actinomycin D, penicillin G, polymyxin, and bacitracin. In addition to preventing the entry of certain compounds, the outer membrane can also be viewed as a means of keeping enzymes of the periplasmic space trapped within the domain of the cell. 

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