The emergence of the mcr-9 gene is quite remarkable.Use of colistin to treat Acinetobacter baumannii infections has led to the development of resistant bacterial strains. They have also developed resistance to the antimicrobial compounds LL-37 and lysozyme, produced by the human immune system. This cross-resistance is caused by gain-of-function mutations to the pmrB gene, a phosphoethanolamine transferase (similar to mcr-1) located on the bacterial chromosome.Not all resistance to colistin and some other antibiotics is due to the presence of resistance genes. Heteroresistance, the phenomenon wherein apparently genetically identical microbes exhibit a range of resistance to an antibiotic, has been observed in some species of Enterobacter since at least 2016 and was observed in some strains of Klebsiella pneumoniae in 2017–2018. In some cases this phenomenon has significant clinical consequences. Inherently resistant
Variable resistance
Aeromonas
Vibrio
Prevotella
Fusobacterium
Escherichia coli

Adverse reactions
The main toxicities described with intravenous treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves), but this may reflect the very high doses given, which are much higher than the doses currently recommended by any manufacturer and for which no adjustment was made for pre-existing renal disease. Neuro- and nephrotoxic effects appear to be transient and subside on discontinuation of therapy or reduction in dose.At a dose of 160 mg colistimethate IV every eight hours, very little nephrotoxicity is seen. Indeed, colistin appears to have less toxicity than the aminoglycosides that subsequently replaced it, and it has been used for extended periods up to six months with no ill effects.
As multi-drug resistant bacteria became more prevalent in the 1990s, colistin started to get a second look as an emergency solution, in spite of toxicity.Colistin has also been used in agriculture, particularly in China from the 1980s onwards. Chinese production for agriculture exceeded 2700 tons in 2015. China banned colistin use for livestock growth promotion in 2016. Biosynthesis
The biosynthesis of colistin requires the use of three amino acids: threonine, leucine, and 2,4-diaminobutryic acid. The linear form of colistin is synthesized before cycliziation. Non-ribosomal peptide biosynthesis begins with a loading module and then the addition of each subsequent amino acid. The subsequent amino acids are added with the help of an adenylation domain (A), a peptidyl carrier protein domain (PCP), an epimerization domain (E), and a condensation domain (C). Cyclization is accomplished by a thioesterase. The first step is to have a loading domain, 6-methylheptanoic acid, associate with the A and PCP domains. Now with a C, A, and PCP domain that is associated with 2,4-diaminobutryic acid. This continues with each amino acid until the linear peptide chain is completed. The last module will have a thioesterase to complete the cyclization and form the product colistin. References
Further reading
Reardon S (December 2015). "Spread of antibiotic-resistance gene does not spell bacterial apocalypse — yet". Nature. doi:10.1038/nature.2015.19037. External links
"Colistimethate sodium". Drug Information Portal. U.S. National Library of Medicine. "Colistin sulfate". Drug Information Portal. U.S. National Library of Medicine. "Colistin topics page (bibliography)". Science.gov.