effect is bactericidal even in an isosmolar environment. Colistin binds to lipopolysaccharides and phospholipids in the outer cell membrane of Gram-negative bacteria. It competitively displaces divalent cations (Ca2+ and Mg2+) from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents and bacterial death. Pharmacokinetics No clinically useful absorption of colistin occurs in the gastrointestinal tract. For systemic infection, colistin must therefore be given by injection. Colistimethate is eliminated by the kidneys, but colistin is eliminated by non-renal mechanism(s) that are as of yet not characterised. History Colistin was first isolated in Japan in 1949 by Y. Koyama, from a flask of fermenting Bacillus polymyxa var. colistinus, and became available for clinical use in 1959. Colistimethate sodium, a less toxic prodrug, became available for injection in 1959. In the 1980s, polymyxin use was widely discontinued because of nephro- and neurotoxicity. As multi-drug resistant bacteria became more prevalent in the 1990s, colistin started to get a second look as an emergency solution, in spite of toxicity. Colistin has also been used in agriculture, particularly in China from the 1980s onwards. Chinese production for agriculture exceeded 2700 tons in 2015. China banned colistin use for livestock growth promotion in 2016. Biosynthesis The biosynthesis of colistin requires the use of three amino acids: threonine, leucine, and 2,4-diaminobutryic acid. The linear form of colistin is synthesized before cycliziation. Non-ribosomal peptide biosynthesis begins with a loading module and then the addition of each subsequent amino acid. The subsequent amino acids are added with the help of an adenylation domain (A), a peptidyl carrier protein domain (PCP), an epimerization domain (E), and a condensation domain (C). Cyclization is accomplished by a thioesterase. The first step is to have a loading domain, 6-methylheptanoic acid, associate with the A and PCP domains. Now with a C, A, and PCP domain that is associated with 2,4-diaminobutryic acid. This continues with each amino acid until the linear peptide chain is completed. The last module will have a thioesterase to complete the cyclization and form the product colistin. References Further reading External links Polymyxin antibiotics Cyclic peptides Polypeptide antibiotics Wikipedia medicine articles ready to translate