Colistin: An Update on the Antibiotic of the 21st Century

Silpak Biswas; Jean-Michel Brunel; Jean-Christophe Dubus; Martine Reynaud-Gaubert; Jean-Marc Rolain

Disclosures

Expert Rev Anti Infect Ther. 2012;10(8):917-934. 

In This Article

Chemistry of Colistin

Colistin is a multicomponent polypeptide antibiotic that is mainly composed of colistin A and colistin B. PMB and colistin (polymyxin E) are secondary metabolite nonribosomal peptides that share a similar primary sequence with the only difference being at position6, which is replaced by D-Phe in PMB and D-Leu in colistin (Figure 2).

Figure 2.

Structure of polymyxin B and colistin. Polymyxin B and colistin (polymyxin E) share a similar primary sequence with the only difference being at position 6, in which D-Phe in polymyxin B is replaced by and D-Leu in colistin.

Colistin sulfate and CMS are the two forms of colistin. CMS is produced by the reaction of colistin with formaldehyde and sodium bisulfite, which leads to the addition of a sulfomethyl group to the primary amines of colistin.[20] Although CMS is the form administered parenterally, it undergoes conversion invivo to form colistin, which is responsible for antibacterial activity, and thus CMS should be considered as an inactive prodrug.[20,21]

The importance of the N-terminal fatty acyl segment for the antimicrobial properties of polymyxins first became evident when polymyxin nonapeptides were identified.[22] Although PMB and colistin nonapeptides lack any direct antimicrobial activity, they possess the same ability to bind lipopolysaccharide (LPS) with an important specificity and perturb the outer membrane (OM) integrity to sensitize Gram-negative bacteria to hydrophobic antibiotics that are not normally active.[22]

Previous studies of the Nα fatty acyl structure–activity relationships (SARs) of PMB and colistin component peptides isolated from cultured strains did not provide any clear and meaningful SAR data.[23] The most comprehensive Nα SAR data have been reported by Sakura and colleagues,[24,25] wherein purified PMB or colistin were converted to nonapeptides by treatment with S-ethyl trifluorothioacetate and used as the starting material.

Recently, Sakura and colleagues have reported a new series of Nα analogs derived by acylation of the tetrakis (Nγ-Troc)-PMB or -colistin nonapeptides with various hydrophobic acids and aliphatic or hydrophobic ring structures.[25] The Nα analogs were tested for their LPS binding affinity and antimicrobial activity against Escherichia coli, and Salmonella enterica and P. aeruginosa. Thus, cyclohexylbutanoyl, 4-biphenylacetyl and 1-adamantaneacetyl-Nα analogs led to comparable activities with respect to the parent compounds (PMB and colistin), with an improved LPS binding affinity.[26–28]

Tsubery et al. adopted a synthetic approach by using a combination of solid-phase linear chain elongation methodology and subsequent cyclization after release.[29] Owing to the presence of a long hydrophobic chain, [Ala]6-PMB was expected to increase the potent antimicrobial activity; nevertheless, neither of the oligoalanyl Nα analogs had significantly better activity than the control product PMB. The N-terminus of the other pair was substituted with the hydrophobic Fmoc group.[25,30,31] This result demonstrates that the hydrophobicity of the Nα substituent group greatly influences the outcome antimicrobial activity and the inherent acute toxicity. Finally, N-terminal modifications of PMB nonapetide have been shown to possess high antibacterial activity and significantly reduced toxicity.[29]

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