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January 9, 2017

Resistance Mechanism to Last-Resort Antibiotic Revealed

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    X-ray crystal structure of the catalytic domain of the MCR-1 protein. [Dr. Phil Hinchliffe/University of Bristol]

    Understanding how microbes acquire resistance genes and the underlying biochemical mechanisms that ensue from that acquisition is our best approach to slowing, reversing, or possibly preventing antibiotic resistance. Last year GEN reported the discovery of a new gene called mcr-1 that was beginning to spread quickly through bacterial populations—leading toward resistance to polymyxin drugs, considered the last line of defense against various strains of pathogenic microbes.

    Now, an international group of investigators, led by University of Bristol scientists who discovered the mcr-1 resistance gene, has just provided the first clues to understanding how the mcr-1 gene protects bacteria from colistin—a polymyxin antibiotic used to treat life-threatening bacterial infections that do not respond to other treatment options.       

    Since the first detection of the mcr-1 gene, it has been detected in common bacteria, such as Escherichia coli, in China, the U.S., and across Europe, first in farm animals and recently—alarmingly—in human patients. The spread of mcr-1 has been linked to the agricultural use of colistin, indicating that transmission between animals and humans may take place. In response to these findings, the Chinese government has now banned the use of colistin in animal feed.

    Colistin acts by binding to and disrupting, the outer surface of bacteria. Bacteria carrying the mcr-1 gene make a protein that modifies the bacterial surface to reduce colistin binding, making the organism resistant.

    "The importance of understanding colistin resistance can hardly be overstated: it is rapidly emerging threat to public health,” noted study co-author Adrian Mulholland, Ph.D., professor and principal investigator for the BristolBridge initiative, based in the School of Chemistry at the University of Bristol.

    In the current study, the researchers used x-ray crystallography to generate detailed pictures of the portion of the MCR-1 protein, which is responsible for the cell-surface modification. With this information in hand, the scientists were able to identify key features that are necessary for it to function. Moreover, they constructed computer models of the chemical reaction that leads to resistance.

    The findings from this study were published recently in Scientific Reports in an article entitled “Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from the Crystal Structure of the Catalytic Domain of MCR-1.”

    "Our results illuminate the structural and (for the first time) mechanistic basis of transferable colistin resistance conferred by mcr-1, thanks to the combination of biological, chemical, and computational expertise brought to bear on this project,” Dr. Mulholland explained.

    This new data provides the first clues as to how mcr-1 acts within the bacterial cell, as well as information essential toward efforts to identify ways of blocking MCR-1 function that could restore the activity of colistin against bacteria carrying mcr-1.

    "We are confident that our findings will drive efforts to understand mcr-1-mediated resistance and ultimately help identify routes toward overcoming MCR-1 activity in harmful bacteria," Dr. Mulholland concluded.

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