Colistin and its role in the Era of antibiotic resistance: an extended review (2000-2019)

Abstract

Increasing antibiotic resistance in multidrug-resistant (MDR) Gram-negative bacteria (MDR-GNB) presents significant health problems worldwide, since the vital available and effective antibiotics, including; broad-spectrum penicillins, fluoroquinolones, aminoglycosides, and β-lactams, such as; carbapenems, monobactam, and cephalosporins; often fail to fight MDR Gram-negative pathogens as well as the absence of new antibiotics that can defeat these "superbugs". All of these has prompted the reconsideration of old drugs such as polymyxins that were reckoned too toxic for clinical use. Only two polymyxins, polymyxin E (colistin) and polymyxin B, are currently commercially available. Colistin has re-emerged as a last-hope treatment in the mid-1990s against MDR Gram-negative pathogens due to the development of extensively drug-resistant GNB. Unfortunately, rapid global resistance towards colistin has emerged following its resurgence. Different mechanisms of colistin resistance have been characterized, including intrinsic, mutational, and transferable mechanisms.In this review, we intend to discuss the progress over the last two decades in understanding the alternative colistin mechanisms of action and different strategies used by bacteria to develop resistance against colistin, besides providing an update about what is previously recognized and what is novel concerning colistin resistance.

Keywords: Colistin; MCR-1; heteroresistance; multidrug resistance; two-component systems.

Figure 1.

(a) Structures of colistin A and B; (b) structures of sodium colistin A and B methanesulphonate. Fatty acid: 6-methyl-octanoic acid for colistin A and 6-methyl-heptanoic acid for colistin B; Thr: threonine; Leu: leucine; Dab: α, γ-diaminobutyric acid. α and γ indicate the respective amino groups involved in the peptide linkage. Adapted from Li et al. [16].

Figure 2.

PRISMA-modified flow diagram of included and excluded studies. Adapted from the PRISMA website (http://www.prisma-statement.org/PRISMAStatement/FlowDiagram) and Liberati et al. [11].

Figure 3.

Action of colistin on the Gram-negative bacterial membrane. The cationic cyclic decapeptide structure of colistin binds with the anionic LPS molecules by displacing Mg²⁺ and Ca²⁺ from the outer cell membrane of Gram-negative bacteria, leading to permeability changes in the cell envelope and leakage of cell contents. LPS: lipopolysaccharides; PG: peptidoglycan; Dab: diaminobutyric acid (Dab); OM: outer membrane; IM: inner membrane. The scheme shows the five different mechanisms of antibacterial activity of colistin, namely; (A) Direct antibacterial colistin activity: the initial fusion of colistin with the bacterial membrane occurs via electrostatic interactions between the cationic diaminobutyric acid (Dab) residues of colistin and anionic phosphate groups on the lipid A moiety of LPS in the outer membrane, thus disrupting the bacterial outer and inner membranes and leads to cell lysis; (B) Anti-endotoxin colistin activity: The lipid A portion of LPS represents an endotoxin in Gram-negative bacteria. Thus, colistin inhibits the endotoxin activity of lipid A by binding to and neutralizing the LPS molecules, thus suppress the induction of shock through the release of cytokines such as tumour necrosis factor-alpha (TNF-α) and Interleukin 8 (IL-8); (C) Vesicle-Vesicle contact pathway: colistin bind to anionic phospholipid vesicles after transiting the OM leads to the fusion of the inner leaflet of the outer membrane with the outer leaflet of the cytoplasmic membrane, leading to loss of phospholipids and cell death; (D) Hydroxyl radical death pathway: Colistin acts via the production of the reactive oxygen species (ROS) this is known as, Fenton reaction, causing damage of DNA, lipid, and protein, and end up with cell death; and (E) Inhibition of respiratory enzymes: the antibacterial colistin activity is via the inhibition of the vital respiratory enzymes. Figure created using Adobe Illustrator version CC 2019 (23.1.0).

Figure 4.

Scheme of colistin binding to lipid A. (A) a Schematic of the transfer of phosphoethanolamine to the 1-PO4 group of Hexa-acylated lipid A in the presence of MCR-1. (B) Models of colistin (blue sticks) binding to lipid A (left) or phosphoethanolamine-1΄-lipid A (right) (spheres coloured green, red, blue, and orange for C, O, N, and P atoms, respectively). a (left), The positively charged Dab colistin residues interact with the negatively-charged 1′ and 4′ phosphate groups of lipid A, reducing the net-negative charge of lipid A. The hydrophobic leucine residues and tail of colistin A bind with the fatty acid tails of lipid A, allowing the uptake of colistin A, and disrupt, the bacterial OM. b (right), a model of colistin binding to phosphoethanolamine-1΄-lipid A indicates the addition of positively charged phosphoethanolamine onto the 1′-PO₄ of lipid A likely interferes with the interaction of positively charged Dab8 and Dab9 side chains with the phosphate group, preventing colistin binding to the outer membrane of GNB. The model B is adapted from Yang et al. [74].