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

Since 2015, the discovery of colistin resistance genes has been limited to the characterization of new mobile colistin resistance () 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.