Colistin (Polymyxin E)

Colistin is a real cyclic lipopeptide antibiotic that fell out of favor for decades due to significant kidney and nerve toxicity, then was revived as a genuine drug of last resort for multidrug-resistant infections — and in 2015-2016, a newly discovered resistance gene (mcr-1) showed that even this last-resort option can spread resistance in an alarming, transferable way.

Mechanism and history

Colistin (polymyxin E) is a cationic cyclic lipopeptide that binds the negatively charged lipid A component of gram-negative bacterial outer-membrane lipopolysaccharide, displacing the calcium/magnesium ions that normally stabilize it, disrupting the outer membrane and then damaging the inner membrane as well. First isolated in 1949 from a Japanese soil bacterium, it saw real clinical use in the 1950s-60s before largely falling out of favor once safer alternatives (aminoglycosides, then later classes) became available.

Real, significant toxicity — and why it's used anyway

Colistin (given as the inactive prodrug colistimethate, which converts to active colistin in the body) carries genuine, dose-dependent nephrotoxicity and neurotoxicity risk — paresthesia, confusion, ataxia, and in severe cases neuromuscular blockade leading to respiratory arrest, particularly in patients with reduced kidney function where the prodrug accumulates unpredictably. It fell out of routine use for exactly this reason, and was revived from the 1990s-2000s onward specifically because multidrug-resistant gram-negative infections — including carbapenem-resistant Enterobacteriaceae — left clinicians with few other options. It is used today as a genuine drug of last resort, not a first choice.

The mcr-1 discovery

Until 2015, all known colistin resistance was chromosomal — meaning it couldn't easily spread from one bacterium to another. Liu et al. (Lancet Infect Dis 2016, published online November 2015) reported the discovery of mcr-1, the first plasmid-mediated (horizontally transferable) colistin-resistance gene, found in E. coli and Klebsiella pneumoniae from pigs, chickens, and human patients in China. Because colistin is often the last option against otherwise-untreatable infections, a resistance mechanism that can jump between bacteria — rather than staying locked in one lineage — was recognized immediately as a serious global-health concern, and mcr-1 was subsequently detected on multiple continents within months of the initial report.

Current status

Still used in hospitals as a last-resort option for resistant gram-negative infections, prescribed and monitored carefully given its toxicity profile. No wellness or grey-market presence.