The History of Colistin Resistance Mechanisms in Bacteria: Progress and Challenges

Abstract

Since 2015, the discovery of colistin resistance genes has been limited to the characterization of new mobile colistin resistance (mcr) gene variants. However, given the complexity of the mechanisms involved, there are many colistin-resistant bacterial strains whose mechanism remains unknown and whose exploitation requires complementary technologies. In this review, through the history of colistin, we underline the methods used over the last decades, both old and recent, to facilitate the discovery of the main colistin resistance mechanisms and how new technological approaches may help to improve the rapid and efficient exploration of new target genes. To accomplish this, a systematic search was carried out via PubMed and Google Scholar on published data concerning polymyxin resistance from 1950 to 2020 using terms most related to colistin. This review first explores the history of the discovery of the mechanisms of action and resistance to colistin, based on the technologies deployed. Then we focus on the most advanced technologies used, such as MALDI-TOF-MS, high throughput sequencing or the genetic toolbox. Finally, we outline promising new approaches, such as omics tools and CRISPR-Cas9, as well as the challenges they face. Much has been achieved since the discovery of polymyxins, through several innovative technologies. Nevertheless, colistin resistance mechanisms remains very complex.

Keywords: colistin history; innovative technologies; mechanisms of action and resistance; polymyxins; technological approaches.

Figure 1

Mechanisms of action and resistance to colistin in Gram-negative organisms. (A): mechanisms of action of colistin, (B): colistin-resistance mechanisms, * on respiratory enzyme inhibition, Hydroxyl radical death, anti-endotoxin activity and the metabolism of lipids and carbohydrates represent the recently described mechanisms of action and resistance, which remain unclear so far; The yellow stars represent mutations resulting in the inactivation of regulatory genes. Green arrows indicate the mechanism of action for a susceptible strain, the red arrows indicate the different pathways involved in colistin resistance, the grey shades demonstrate the differences in the gene expression between the mechanism of action and resistance

Figure 2

Timeline of the main events related to colistin, from the discovery of colistin to the development of resistance (A) represents the described mechanisms, the green arrows symbolize the enzymatic mechanisms, the orange arrows symbolize the chromosomal mechanisms. (B) represents the chronology of colistin.