Colistin: Lights and Shadows of an Older Antibiotic

Abstract

The emergence of antimicrobial resistance represents a serious threat to public health and for infections due to multidrug-resistant (MDR) microorganisms, representing one of the most important causes of death worldwide. The renewal of old antimicrobials, such as colistin, has been proposed as a valuable therapeutic alternative to the emergence of the MDR microorganisms. Although colistin is well known to present several adverse toxic effects, its usage in clinical practice has been reconsidered due to its broad spectrum of activity against Gram-negative (GN) bacteria and its important role of "last resort" agent against MDR-GN. Despite the revolutionary perspective of treatment with this old antimicrobial molecule, many questions remain open regarding the emergence of novel phenotypic traits of resistance and the optimal usage of the colistin in clinical practice. In last years, several forward steps have been made in the understanding of the resistance determinants, clinical usage, and pharmacological dosage of this molecule; however, different points regarding the role of colistin in clinical practice and the optimal pharmacokinetic/pharmacodynamic targets are not yet well defined. In this review, we summarize the mode of action, the emerging resistance determinants, and its optimal administration in the treatment of infections that are difficult to treat due to MDR Gram-negative bacteria.

Keywords: antimicrobial resistance; antimicrobials; colistin; lipopeptide.

Figure 1

Colistin prodrug structure. Two-dimensional representation of colistin methanesulfonate molecule highlighted the five methanesulfonate groups (inside the purple dotted circles) responsible for the difference between active compound and its colistimethate sodium (prodrug) form. This 2D representation was performed with MolView v2.4 online tool (https://molview.org/ accessed on 1 January 2024).

Figure 2

Colistin mechanism of action and SMH model. Schematic representation of colistin’s effect on Gram-negative bacteria. (a) Colistin drug acts by competition with Ca²⁺ and Mg²⁺ ions, causing their displacement and leading to (b) formation of pores. Colistin goes through the peptidoglycan barrier reaching the inner membrane where it acts by displacing Ca²⁺ and Mg²⁺ ions. All the structural alteration, induced by colistin action on membranes or colistin intracellular accumulation, leads to cell death (c). The three-dimensional model of colistin was generated with MolView v2.4 online tool (https://molview.org/ accessed on 1 January 2024). This figure was created in BioRender.com.

Figure 3

Mechanism of resistance to colistin. Schematic representation of principal colistin resistance mechanisms among Gram-negative bacteria: (i) modification of LPS structure mediated by chromosomal mutation; (ii) modification of LPS structure mediated by plasmid-resistance; (iii) loss of LPS structure; (iv) overexpression of efflux pumps.