Polymyxins are antibiotics that mainly fight gram-negative bacteria. However, the active substances act only on bacteria located outside the body cells. The basis of their effectiveness is their reaction with the phospholipids of bacterial cell membranes.
What are polymyxins?
Polymyxins are antibiotics that fight mainly Gram-negative bacteria. Polymyxins represent intricately branched polypeptides, which usually consist of ten amino acids. They have hydrophobic fatty acids at the end. The molecular structure enables the formation of a polarity corresponding to that of the phospholipids of the cell membranes. As a result, these molecules are able to interact with phospholipids and destroy their structure. As a result, the bacterial cell membrane dissolves. When it is completely destroyed, cell death of the bacterium occurs. However, polymyxins only reach bacteria positioned outside the cell. If the bacteria have already passed through the membrane of the body cell, they can no longer be destroyed by these agents. Two active ingredients of polymyxins are mainly used. One is polymyxin B and the other is colistin. The mode of action of both substances is similar. However, the polymyxins cannot be absorbed parenterally (bypassing the intestine) because they then have a neurotoxic and damaging effect on the kidneys. In more recent applications, colistin is therefore applied in the form of a prodrug as colistimethate sodium (CMS).
Pharmacologic action
Polymyxins are applied to control mainly pathogenic Gram-negative bacteria. Gram-negative and Gram-positive bacteria differ in the structure of their cell membranes. According to the staining method developed by the Danish bacteriologist Gram, the two groups of bacteria can be easily distinguished from each other. A basic dye is used to stain the cell membrane by forming a complex. Gram-positive bacteria show staining, while Gram-negative bacteria cannot be stained. Gram-positive bacteria have a thick murein envelope of peptidoglycans in their cell membrane, while Gram-negative bacteria have only a thin murein layer. These differences influence the sensitivity of the bacteria to various antibiotics. Thus, a decision for or against certain antibiotics can already be made by a quick determination of the Gram stain. Due to their polarity, polymyxins react mainly with phospholipids bound to polysaccharides. Thus, chemical bonds are formed between polymyxins and lipopolysaccharides (LPS). Due to the thin murein layer in gram-negative bacteria, the LPS are better reached by the polymyxins in these bacteria. As a result, the cell membrane is initially destroyed until the entire cytoplasmic content is released, causing the bacterial cell to die. The sensitivity of the bacteria to the polymyxins increases with the content of phospholipids in the cell membrane. Thus, the cell membranes of very sensitive bacteria were found to bind more polymyxins than less sensitive ones. Chemical modification of the active ingredients, such as removal of the terminal fatty acid, can also reduce efficacy. It has also been found that the higher the concentration of antibiotics, the better the bacteria are fought. In studies, blistering of the bacterial membrane was observed, leading to complete destruction. If the concentration was too low, the membrane could not be completely dissolved and the bacterium survived. In the treatment, it does not matter whether the bacteria are dormant or just dividing. Equally good control is possible in both phases.
Medical application and use
Both polymyxin B and colistin have the same spectrum of activity. Among others, they control particularly well such Gram-negative bacteria as Pseudomonas aeruginosa, Escherichia coli, Enterobacter spp, Pasteurella spp, Haemophilus spp, Vibrio spp, Bordetella spp, or Aerobacter. Particularly sensitive bacteria that respond well to treatment include Acinetobacter spp, Bordetella bronchiseptica, Escherichia coli, Klebsiella pneumoniae, Histophilus somni, Taylorella equigenitalis, Pasteurella multocida, or Pseudomonas aeruginosa. Resistance to the polymyxins may also occur. However, these rarely occur.Resistance can result from changes in the active ingredients on the bacterial surface, from inhibition of entry into the cell membrane, or from changes in the bacterial surface. For example, some bacteria form digestive enzymes that break down the polypeptides of the polymyxins already on the cell surface. Furthermore, some bacteria contain certain pumps which transport antibiotics that have penetrated the cell out of the cell again. A change in the bacterial surface, which can be seen, for example, in a lower density of phospholipids, can also contribute to resistance. The main polymyxins used are polymyxin B or colistin. The mode of action of both substances is the same. However, colistin can be used directly only in ointments, in aerosols for inhalation therapy, or orally for intestinal treatment. It is hardly absorbed in the intestine, so it can only be administered parenterally (such as intravenously) for systemic use. However, pure colistin has neurotoxic and toxic effects against the kidneys when absorbed parenterally. However, as a prodrug, it can be absorbed without complications as colistimethate sodium (CMS).
Risks and side effects
As mentioned earlier, colistin should not be taken parenterally, i.e., bypassing the intestine, because neurotoxic and nephrotoxic effects may then occur. This also applies to other polymyxins. However, oral intake of colistin is not suitable for systemic use because it is hardly absorbed through the intestine. However, as a prodrug in the form of colistimethate sodium (CMS), it can be used systemically.
