Polymyxins are

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

s. Polymyxins B and E (also known as colistin) are used in the treatment of Gram-negative bacterial infections. They work mostly by breaking up the bacterial

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

. They are part of a broader class of molecules called

nonribosomal peptide Nonribosomal peptides (NRP) are a class of peptide secondary metabolites, usually produced by microorganisms like bacteria and fungi. Nonribosomal peptides are also found in higher organisms, such as nudibranchs, but are thought to be made by bacter ...

s. They are produced in nature by

Gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

such as '' Paenibacillus polymyxa''.

Medical use

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 ''Pseudomonas aeruginosa'' is a common encapsulated, gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, ''P. aerugi ...

'' or carbapenemase-producing

Enterobacteriaceae Enterobacteriaceae is a large family (biology), family of Gram-negative bacteria. It was first proposed by Rahn in 1936, and now includes over 30 genera and more than 100 species. Its classification above the level of family is still a subject ...

. Polymyxins have less effect on Gram-positive organisms, and are sometimes combined with other agents (as with

trimethoprim/polymyxin The drug combination trimethoprim/polymyxin (INNs, trade name Polytrim) is an antimicrobial solution for topical ophthalmic use in the treatment of acute bacterial conjunctivitis Conjunctivitis, also known as pink eye, is inflammation of th ...

) to broaden the effective spectrum. Polymyxins B are not absorbed from the gastrointestinal tract, so they are only administered orally if the goal is to disinfect the GI tract. Another

route of administration A route of administration in pharmacology and toxicology is the way by which a medication, drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance i ...

is chosen for systemic treatment, 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.

Mechanism of action

After binding to

lipopolysaccharide Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...

(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 A detergent is a surfactant or a mixture of surfactants with cleansing properties when in dilute solutions. There are a large variety of detergents, a common family being the alkylbenzene sulfonates, which are soap-like compounds that are more ...

-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 that 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 bacterial plasmids in ''Enterobacteriaceae''.

Chemistry

Polymyxins are a group of cyclic non-ribosomal polypeptide (NRPs) which are biosynthesized by bacteria belonging to the genus '' Bacillus'', more specifically the subgenus '' Paenibacillus''. Polymyxins consist of 10

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

residues, six of which are L-α,γ- diaminobutyric acid (L-DAB). The DAB residues cause polymyxins to have multiple positively charged groups at physiological pH. Seven amino acid residues form the main cyclic component, while the other three extend from one of the cyclic residues as a linear chain terminating in either 6-methyloctanoic acid or 6-methylheptanoic acid at the

N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

. During cyclization, residue 10 is bound to the bridging residue 4. The amino acid residues and DAB monomers are generally in the L (levo) configuration, however certain strains such as P. polymyxa PKB1 have been observed to incorporate DAB with the D (dextro) configuration at position 3 producing variations of polymyxin B. Polymyxin M is also known as "mattacin".

Biosynthesis

The polymyxins are produced by

synthetase systems in

such as '' Paenibacillus polymyxa''. Like other NRPs, polymyxins are assembled by synthetases with multiple modules, each containing a set of enzyme domains that sequentially operate on the growing chain by adding the next residue and extending the chain through peptide-bond formation and condensation reactions. The final steps involve a thioesterase domain at the C-terminal of the last module to cyclize the molecule and liberate the chain from the enzyme.

Research

Polymyxins are used to neutralize or absorb LPS contaminants in samples, for example in immunological experiments. Minimization of LPS contamination can be important because LPS can evoke strong reactions from immune cells, distorting experimental results. By increasing permeability of the bacterial membrane system, polymyxin is also used in clinical work to increase the release of secreted toxins, such as ''Shiga'' toxin, from ''Escherichia coli''. The global problem of advancing antimicrobial resistance has led to a renewed interest in their use.

References