ABSTRACT
The polymyxins are a group of antibiotics, named A, B, C, D, E, and so on, which were first isolated in 1947 from a spore-bearing soil bacillus (Paenibacillus polymyxa). Although several polymyxins exist, only polymyxin B and E (the latter also known as colistin) are used clinically. The polymyxins, like bacitracin (see Chapter 83, Bacitracin and gramicidin), have a polypeptide structure. The structures of polymyxin B and colistin are shown in Figure 81.1a. Given that both polymyxins are produced by fermentation, it is not surprising that they are a mixture of several components, with two major components for each of polymyxin B and colistin (see Figure 81.1a). Because of the multicomponent nature and the absent or wide limits on the allowed content of the components as specified in the United States and European Pharmacopoeias (European Pharmacopoeia, 2014b, 2015; Nation et al., 2015; US Pharmacopeial Convention, 2016a, 2016b), there is no accurate molecular weight for either polymyxin B or colistin. However, the molecular weights for polymyxin B1, polymyxin B2, colistin A (polymyxin E1), and colistin B (polymyxin E2) are 1202, 1188 (Orwa et al., 2001b), 1170, and 1156 (Li et al., 2001a; Orwa et al., 2001a), respectively. Clinically, polymyxin B is administered parenterally as its sulfate salt. Although colistin sulfate also exists commercially, this is not the form for parenteral administration. Instead, colistin is administered parenterally in the form of the sodium salt of colistin methanesulfonate (CMS) (also known as colistimethate). It is important to note that the methanesulfonate of colistin is not a salt as such; it is a chemical derivative in which methanesulfonate moieties are attached through covalent bonds to the primary amines in colistin (Figure 81.1b). The structure shown in the figure has one methanesulfonate moiety attached to each of the five primary amines of colistin; this has been the perceived structure of CMS for decades. However, recent studies have revealed greater chemical complexity. Some primary amines may not be derivatized, whereas others may have two methanesulfonate groups attached (Kenyon, 2015). The United States and European Pharmacopoeias do not specify limits for the numerous possible components of CMS (European Pharmacopoeia, 2014a; Nation et al., 2015; US Pharmacopeial Convention, 2016b). Polymyxin B and colistin are cationic (by virtue of the primary amines that are ionized [i.e. carry positive charges] at physiologic pH). In contrast, CMS is anionic [by virtue of the methanesulfonate groups which are ionized (i.e. carry negative charges) at physiological pH]. As discussed later and in section 2, Antimicrobial activity, and section 5, Pharmacokinetics and pharmacodynamics, CMS is an inactive prodrug of colistin (Bergen et al., 2006). (a) Structures of colistin A and B and polymyxin B1 and B2. In polymyxin B, <sc>d</sc>-Phe (phenylalanine) replaces the <sc>d</sc>-Leu (leucine) marked with the asterisk; (b) structures of colistin methanesulfonate A and B. Fatty acid: 6-methyloctanoic acid for colistin A and 6-methylheptanoic acid for colistin B. Thr: threonine; Leu: leucine; Dab: α,γ-diaminobutyric acid. α and γ indicate the −NH<sub>2</sub> involved in the peptide linkage. https://s3-euw1-ap-pe-df-pch-content-public-p.s3.eu-west-1.amazonaws.com/9781315152110/08d8042d-9481-4a8d-8c27-9bd589f6de6b/content/fig81_1.tif" xmlns:xlink="https://www.w3.org/1999/xlink"/>
