Polymyxins are antibiotics, with a general structure consisting of a cyclic peptide with a hydrophobic tail. They disrupt the structure of the bacterial cell membrane by interacting with its phospholipids. They are produced by nonribosomal peptide synthetase systems in Gram-positive bacteria such as Paenibacillus polymyxa and are selectively toxic for Gram-negative bacteria due to their specificity for the lipopolysaccharide molecule that exists within many Gram-negative outer membranes.
Polymyxins B and E (also known as colistin) are used in the treatment of Gram-negative bacterial infections. The global problem of advancing antimicrobial resistance has led to a renewed interest in their use recently.
Polymyxin M is also known as "mattacin".
Polymyxin antibiotics are relatively neurotoxic and nephrotoxic, so are usually used only as a last resort if modern antibiotics are ineffective or are contraindicated. Typical uses are for infections caused by strains of multiple drug-resistant Pseudomonas aeruginosa or carbapenemase-producing Enterobacteriaceae.
Polymyxins B are not absorbed from the gastrointestinal tract, so another route of administration must be chosen, e.g., parenteral (often intravenously) or by inhalation. They are also used externally as a cream or drops to treat otitis externa (swimmers ear). and as a component of triple antibiotic ointment to treat and prevent skin infections.
Because they also bind and cause toxicity in host cells, clinically, polymyxins are used only as a last resort.
Mechanism of action
After binding to lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria, polymyxins disrupt both the outer and inner membranes. The hydrophobic tail is important in causing membrane damage, suggesting a detergent-like mode of action.
Removal of the hydrophobic tail of polymyxin B yields polymyxin nonapeptide, which still binds to LPS, but no longer kills the bacterial cell. However, it still detectably increases the permeability of the bacterial cell wall to other antibiotics, indicating it still causes some degree of membrane disorganization.
Gram-negative bacteria can develop resistance to polymyxins through various modifications of the LPS structure that inhibit the binding of polymyxins to LPS.
Antibiotic resistance to this drug has been increasing, especially in southern China. Recently the gene mcr-1, which confers the antibiotic resistance, has been isolated from Enterobacteriaceae bacteria plasmids which will increase the likelihood of its spread globally.
Use in biomedical research
Polymyxins are used to neutralize or absorb LPS, which contaminates samples intended for use in, e.g., immunological experiments. Minimization of LPS contamination can be important because LPS can evoke strong reactions from immune cells and, therefore, distort experimental results.
By increasing permeability of the bacterial membrane system, polymyxin is also used in clinical work to increase release of secreted toxins, such as Shiga toxin from Escherichia coli.
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