The polymyxin group

It soon became apparent that the three groups were dealing with closely related substances when it was possible to prove the identity of B. aerosporus and B. poly my All three antibiotics acted selectively against gram- 

Another strain of B. polymyxa, isolated from soil in Moscow in 1958, produced a different type of polymyxin, called polymyxin 

The polymyxins—The members of the polymyxin group have very similar chemical and physical properties. They are all cyclic basic polypeptides containing characteristic constituents such as a,y-diaminobutyric acid, i,-threonine and a fatty acid. They differ by the presence or absence of the additional amino acids D-leucine, L-leucine, L-isoleucine, n-phenylalanine, D-valine and D-serine, as well as by the nature of the fatty acid Table 1.11). Their molecular weights are aU in the region of 1,200. Although several structural features had been established very early - the exact 

The molecular weight of polymyxin B was shown by the method of partial substitution to be 1,150 d 10 per cent. Quantitative amino acid analysis yielded the amino acids a,y-diaminobutyric acid, L-threonine, D-phenylalanine and L-leucine in the molar proportions 6 2 1 1. Because no free a-carboxyl- and no free a-amino groups could be detected, polymyxin Bi had to be of a cyclic nature . Neither pepsin nor trypsin was found to attack the molecule and therefore partial hydrolysis and separation of the fragments was used for the elucidation of the structure. Of the 14 fragments isolated and identified, seven key peptides were necessary for proposing four tentative structures for polymyxin Two were formulated with a ring 

Recently it has been reported that polymyxin Bj differs from polymyxin Bj only in the replacement of the ( + )-6-methyloctanoic acid by 6-methylheptanoic acid . Polymyxin A and C are only known in their qualitative, and polymyxin D and M only in their quantitative amino acid composition Table 1.11). Polymyxin M is at present being studied intensively . 

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The antibacterial activity of five members (A to E) of the polymyxin group is of a similar nature. However, they are all nephrotoxic although this effect is much reduced with polymyxins B and E (colistin). Colistin sulphomethate sodium is the form of colistin used for parenteral administration. Sulphomyxin sodium, a mixture of sulphomethylated polymyxin B and sodium bisulphite, has the action and uses of polymyxin B sulphate, but is less toxic. 

Threonine and a,7-diaminobutyric acid are present within the structure of these antibiotics. The distinguishing feature of the polymyxine group is in that they contain 4-5 free / amine groups of a,7-diaminobutyric acid, which gives them the property of a cationic detergent able to form complexes with phospholipids of cellular membranes. All polymyxines are similar in term of antibiotic action. 

Figure 1.7. The structures of the known members of the polymyxin group...

It is still premature to give a clear correlation between structure and activity in the polymyxin group, because most published data on antimicrobial activity have been obtained either with impure material or with mixtures of the different individuals. Also the definition of potency differs for those antibiotics which were considered to be different up to now. But the synthesis " of the four compounds originally proposed by Hausmann with a D-a,y-diaminobutyric acid adjacent to the fatty acid and the synthesis of polymyxin Bj and colistin A have given some clues in these respects Table 1.12). 

The discovery of antibiotic substances secreted by various strains of Bacillus polymyxa was simultaneously made in 1947 by Benedict and Langlykke (58) and by Stansly, Shepherd, and White (545). The latter workers, in particular, described the production and purification of a biologically active substance, which they named polymyxin. At almost the same time, Ainsworth, Brown, and Brownlee (16) announced the discovery of the production of a new antibiotic called aerosporin, by B. aerosporus, a species closely related to B. polymyxa. Later aerosporin was classified with the polymyxin group under the name polymyxin A. Actually, it appears that there are several polymyxins, each synthesized by different strains of B. polymyxa (326,327). A given strain, in general, synthesizes only one polymyxin (327). 

The peptide circulin, which was isolated from a culture of Bacillus circulans (431) should be placed in the polymyxin group. This antibiotic, active preferentially on Gram-negative bacteria (430) is a cyclic, basic heteromeric peptide, containing, as do polymyxins, L-a,7-diaminobutyric acid, threonine, and an optically active isomer of pelargonic acid which is probably (-b)6-methyloctanoic acid. In addition, circulin contains D-leucine (458). The composition (Table IX) of circulin is close to that of polymyxins A and E. However, this antibiotic, unlike polymyxin A, is inactivated by the enzyme lipase (458). Paper chromatography (173) distinguishes circulin from polymyxins A and E. 

The polymyxin group of antibiotics includes the closely related peptides polymyxin A (Ainsworth et al., 1947), polymyxin and (Brownlee and Jones, 1948), polymyxin C (Brownlee and Jones, 1948), polymyxin D (Benedict and Langlykke, 1947 Stansly et al., 1947), polymyxin Ej and Eg (Brownlee and Jones, 1948 Koyama, 1952), polymyxin M (Ilyinskaya and Rossovs-KAYA, 1958 Khoklov et al., I960), and circuHn A and B (Murray et al, 1949)-Polymyxin A was originally named aerosporin, and the antibiotic cohstin (also called colimycin) is now known to be identical with polymyxin E. Polymyxins A, C and D have not been well characterized and may represent mixtures of substances. 

The antibiotics of the polymyxin group are branched, cyclic decapeptides containing several residues of L-2,4-diaminobutyrate, at least one residue of... 

Polymyxins are a group of antibiotics which disrupt bacterial cell membranes. Two mechanisms of acquired resistance to the polymyxins have been identified (Russell Chopra 1996). 

Erythromycin, a macrolide antibiotic, lacks a significant chromophore. Detection sensitivity was enhanced by using a wavelength of 200 nm and selecting an injection solvent of lower conductivity than the BGE. In order to facilitate the separation of erythromycin and its related substances, 35% (v/v) ethanol was incorporated into a 150 mM phosphate buffer pH 7.5. Resolution of all of the compounds was achieved in approximately 45 min. The method was employed as an assay method for erythromycin and for impurity determination. Peptide antibiotics, such as colistin and polymyxin, are mixtures of many closely related compounds. A validated CZE method for impurity analysis of polymyxin B was described, employing 130 mM triethanolamine-phosphate buffer at pH 2.5 to reduce the adsorption of analyte onto the capillary wall. Methyl-/l-cyclodextrin (M-/1-CD) and 2-propanol were found to be necessary for selectivity enhancement. Using similar buffer additives, the same group developed and validated a method for colistin analysis. ... 

The polymyxins are a group of antibiotics produced by Bacillus polymyxa. Polymyxin B (Aerosporin) and co-Ustin (polymyxin E, Coly-Mycin) are used in the treatment of bacterial diseases. 

The polymyxins are a group of basic peptides active against gram-negative bacteria and include polymyxin and polymyxin E (colistin). Polymyxins act like cationic detergents. They attach to and disrupt bacterial cell membranes. They also bind and inactivate endotoxin. Gram-positive organisms, proteus, and neisseria are resistant. 

Helander, I., Kilpelainen, I., Vaara, M. Increased substitution of phosphate groups in lipopolysac-charides and lipid A of the polymyxin-resistant pmrA mutants of Salmonella typhimurium a 31P-NMR study. Mol Microbiol 11 (1994) 481—487. 

Fig. 12.6 A transfer-NOE derived space-fill model of the polymyxin B (PMB) -lipid A complex. Bidendate ionic H-bonds between pairs of the y-amino groups of Dab residues of PMB and the phosphates of lipid A, as well as hydrophobic interactions between the methyloctanoate group of PMB and the polyacyl domain of lipid A stabilize the interactions...

Resistance to polymyxins. The polymyxins (A, B, C, D, E) are a group of antibiotics obtained from Bacillus polymyxa [145]. Polymyxin E is referred to as colistin. These antibiotics are extremely active against strains of Ps. aeruginosa but have the disadvantage of certain toxicity problems. The action of polymyxin is on the cytoplasmic membrane involving the phopholipid components [65,146]. 

Polymyxins. Polymyxin B [1404-26-8] and polymyxin E [1066-17-7] (colistin) are the only medically important antibacterials from a group of some thirty closely related cyclic decapeptide antibiotics in the polymyxin family, some of which are given in Table 2. Most family members contain a seven amino acid ring attached to a three amino acid tail, to which is attached a fatty acyl group. The octapeptins have a tail containing a single amino acid. Each antibiotic contains several L-a-y-diaminobutyric acid [1758-80-1], C4H10N2O2, (Dab) residues, L-threonine [72-19-5], at least one D-amino acid, and one of a very limited list of fatty acids. 

The bacitracin zinc and polymyxin B sulfate ophthalmic ointment USP is a sterile antimicrobial ointment formulated for ophthalmic use. Bacitracin zinc is the zinc salt of bacitracin, a mixture of related cyclic polypeptides (mainly bacitracin A) produced by the growth of an organism of the lichenlformis group of Bacillus subtilis var Tracy. It has a potency of not less than 40 bacitracin units per milligram. Polymyxin B sulfate is the sulfate salt of... 

Brevin, Brevolin and Edein, three peptide antibiotics with structures yet unknown, are not in clinical use Table 1.4). Tyrothricin consists of a whole group of chemically and biologically closely related individuals, a feature known for the polymyxins, the bacitracins and other peptide-type antibiotics. The tyrothricin group is interesting not only because of its clinical application, but also from a historical viewpoint. Tyrothricin was the second antibiotic found, 10 years after the discovery of penicillin, in a direct search for antibiotic substances. As the first antibiotic of strictly peptide nature, it... 

The whole character of the molecule seems to be responsible for the biological activity of the polymyxins. One might expect that a conformation similar to gramicidin S is responsible, in so far as the hydrophilic A -amino groups are aggregated on one side of the molecule and the hydrophobic side-... 

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