Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance

Abstract

Following their initial discovery in the 1940s, polymyxin antibiotics fell into disfavor due to their potential clinical toxicity, especially nephrotoxicity. However, the dry antibiotic development pipeline, together with the rising global prevalence of infections caused by multidrug-resistant (MDR) Gram-negative bacteria have both rejuvenated clinical interest in these polypeptide antibiotics. Parallel to the revival of their use, investigations into the mechanisms of action and resistance to polymyxins have intensified. With an initial known effect on biological membranes, research has uncovered the detailed molecular and chemical interactions that polymyxins have with Gram-negative outer membranes and lipopolysaccharide structure. In addition, genetic and epidemiological studies have revealed the basis of resistance to these agents. Nowadays, resistance to polymyxins in MDR Gram-negative pathogens is well elucidated, with chromosomal as well as plasmid-encoded, transferrable pathways. The aims of the current review are to highlight the important chemical, microbiological, and pharmacological properties of polymyxins, to discuss their mechanistic effects on bacterial membranes, and to revise the current knowledge about Gram-negative acquired resistance to these agents. Finally, recent research, directed towards new perspectives for improving these old agents utilized in the 21st century, to combat drug-resistant pathogens, is summarized.

Keywords: Gram-negative pathogens; antibiotic resistance; colistin; lipopolysaccharide; mcr; outer membrane; polymyxins.

Figure 1

(a) Representation of the chemical structures of polymyxin B and colistin, with components B1, B2, E1, and E2, as well as colistimethate. The shaded boxes represent the fixed portions of the molecule, while the white boxes represent the structures that differ among polymyxin B, colistin, and/or colistimethate. The numbers in the blue circles correspond to the numbering of the amino acids from 1 to 10. The linear part of the molecule consists of a tripeptide (amino acids 1–3), while the cyclic part consists of a heptapeptide (amino acids 4–10). Dab = L-α,γ-diaminobutyric acid, Thr = Threonine; Leu = Leucine. (b) The groups A, B, and C in section (a) are described, and they represent the chemical moieties with variation between the polymyxins B1, B2, E1, E2 or between them and the prodrug colistimethate.

Figure 2

A schematic representation of a Gram-negative cell wall with outer membrane composition. The inner leaflet consists of phospholipids, whereas the outer leaflet shows lipopolysaccharides, lipoproteins and porins. Lipopolysaccharide components are also shown. Cationic polymyxins bind to the negatively charged components of lipopolysaccharides.