mcr-1 mediated resistance to colistin could be reliant on zinc ions, as a new study seems to suggest.
The paper, which was published on the 6th January 2017 in Nature, gives us the first solid evidence for how mcr-1 mediated colistin resistance occurs. This research follows previous work which highlighted that mcr-1 is the first known colistin-resistance gene which can be passed between bacteria including E. coli and Klebsiella pneumoniae.
Colistin is an antibiotic often used as a last-line drug against multi-drug resistant, gram-negative bacteria. It works by attaching to the outer membrane of its target bacteria, disrupting the integrity of the membrane and causing leakage of the bacteria’s intracellular contents, killing the organism.
However, we’re starting to see an increase in the number of gram-negative, multi-drug resistant bacteria which also show resistance to colistin. These organisms can cause sepsis, wound infections and UTIs, to name just a few conditions, and when no antibiotics can work against them, they become both much more difficult to deal with, and much more dangerous.
Colistin resistance occurs when gram-negative bacteria acquire the mcr-1 gene. This lets them produce an enzyme called MCR-1, which acts to allow a phosphoethanolamine group to be transferred onto the glucosamine saccharide of lipid A, a structure found on the bacteria’s outer membrane. This transfer essentially stops colistin from being able to bind to the surface of the bacteria, so it can’t do anything against the organism.
By using X-ray scans, the team were able to generate images of MCR-1’s catalytic subunit (the part of the enzyme which is responsible for allowing the modification).
They were then able to show that the MCR-1 enzyme needs zinc ions to carry out its function – in other words, that MCR-1 is a metalloprotein. They confirmed this need by reducing zinc levels available to E. coli possessing the mcr-1 gene, then testing what effect this had on colistin’s ability to kill them. They found that this led to a decrease in colistin’s MIC value – a lower concentration was needed to inhibit the growth of the E. coli, suggesting that reducing availability of zinc made the organisms more susceptible to the antibiotic.
The importance of zinc was also shown when the team substituted zinc ions for alanine – again, this resulted in a lower colistin MIC value.
The research team was also able to generate theoretical models to show how the transfer process catalysed by MCR-1 occurs.
The information provided by this study represents a vital step in fully understanding the mechanisms behind the bacterial modification caused by MCR-1, and therefore puts us in a better position to find ways to overcome colistin resistance.
A co-author of the paper, Dr. Adrian Mulholland, stated “We are confident that our findings will drive efforts to understand mcr-1 mediated resistance and ultimately help identify routes towards overcoming MCR-1 activity in harmful bacteria.”