16/4/2018 Can colistin resistance be reversed?

Friday, 13 April 2018 16:28

Can colistin resistance be reversed?

Written by Julie Wolf

Published in mBiosphere
Colistin resistance was only discovered in bacteria in 2015, but it has quickly become a major factor in infectious
disease, spreading quickly between different countries and bacterial species. Since the discovery of the mcr-1 gene
that confers colistin resistance, further studies have revealed additional plasmid-borne genes that contribute to
colistin resistance—mcr-2 through mcr-5—though mcr-1 remains the most widespread form of transmissible colistin
resistance. How does mcr-1 allow bacteria to escape colistin resistance, and can that mechanism be reversed? Two
new reports from ASM journals provide the molecular foundation for understanding MCR-1 resistance and designing
MCR-1 inhibitors.
mBio: An evolutionarily conserved mechanism for intrinsic and transferable polymyxin resistance
To understand the mBio study’s implications, it’s important to
know how colistin, a polymyxin drug, acts to kill bacteria.
Polymyxins are most effective against gram-negative bacteria,
because of their interactions with lipopolysaccharide (LPS) on
the outer bacterial envelope. The negative charge of LPS
contributes to the negative charge of the bacterial surface,
which allows the positively charged polymyxins to interact with
and disrupt the bacterial membrane. MCR-1 transfers a
positively charged phosphoethanolamine (pEtN) onto the LPS
molecule, decreasing the bacterial surface charge and
lowering its affinity for polymyxin interaction (see figure, right).
Many bacteria modify LPS with pEtN and other modifications;
these modifications influence membrane architecture. The
research team, led by first author Yongchang Xu and senior
scientist Youjun Feng, compared EptA, a Neisseria
chromosomally encoded pEtN-transferase that confers Schemes of chemical mechanism and colistin resistance for
intrinsic resistance to polymyxin drugs, to MCR-1 and MCR-2. MCR-1, MCR-2, and EptA. (A) Chemical reaction for the
They found structural similarities between EptA, MCR-1, and transfer to pEtN to lipid A of LPS by MCR2. (B) The reaction
MCR-2, including a conserved pEtN substrate-binding cavity, begins with removal of pEtN from phosphoethanolamine (PE)
but found that swapping different structural domains between and (C) then transfers it to lipid A. (D) Cartoon of the model
EptA and MCR- decreased function. This suggests that EptA, proposed for the bacterial surface structure of colistin-sensitive
MCR-1, and MCR-2 share a similar mechanism in pEtN E. coli. (E) Working model for structural modification of LPS on
catalysis but have slightly different structural requirements for bacterial surface in colistin resistance. (F) Chemical structure of
substrate recognition. colistin. Source.
The structure-function studies are the foundation for designing
inhibitors that may stop MCR-1 function and rescue colistin antibacterial activity. Good news has come on that front

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16/4/2018 Can colistin resistance be reversed?

already, with a report from Antimicrobial Agents and Chemotherapy that describes a new potential MCR-1 inhibitor.
AACJournal: Pterostilbene, a potential MCR-1 inhibitor that enhances the efficacy of polymyxin B
Researchers screened 115 natural compounds to synergize with polymyxin activity against mcr-1-positive clinical
isolates. First author Yonglin Zhou, senior scientist Xumeng Deng, and their colleagues looked for compounds that
could potentiate the activity of either polymyxin E (another name for colistin) or polymyxin B, a close chemical
relative with the same antibacterial mechanism. The authors found that the plant-derived compound pterostilbene
decreased the minimal inhibitory concentration of polymyxin B for mcr-1-positive E. coli strains from 8 to 1 μg/ml.
The compound on its own had no effect on microbial growth.
The authors showed that using pterostilbene and polymyxin B together increased treatment efficacy in mice infected
with one of the same mcr-1-expressing E. coli strains. The combination therapy reduced the bacterial loads in the
spleen and liver 10-fold compared to mice treated with only polymyxin B, and increased mouse survival in a lethal
sepsis model of infection. The authors propose using pterostilbene, safe for human consumption at doses up to 250
mg per day, in combination with polymyxins to treat colistin-resistant Enterobacteriaceae.
Zhou et al. propose that the pterstilbene inhibits MCR-1
activity, allowing the polymyxin to resume its normal
interactions with the bacterial outer membrane, though is yet
to be definitively shown. If true, combining this new compound
(molecular structure shown at right) with the molecular
interaction data from above may allow scientists to chemically
modify the pterostilbene to improve its MCR-1 inhibition.
Regardless, this discovery shows promise to extend the
usefulness of colistin despite the continued spread of plasmid-
The chemical structure of pterostilbene. Source.
borne resistance, as scientists continue to search for new
antibacterial compounds to use against drug-resistant
infections.
For the latest concerning polymyxin B, polymyxin E, and colistin, check out a recent review from Clinical
Microbiology Reviews.
ClinMicroRev: Polymyxins: Antibacterial activity, susceptibility testing, and resistance mechanisms
encoded by plasmids or chromosomes.
Want to discuss colistin resistance with world-class researchers?
REGISTER TODAY FOR ASM MICROBE 2018 TO MEET WITH FELLOW SCIENTISTS AND DISCUSS CUTTING-
EDGE RESEARCH!

Last modified on Friday, 13 April 2018 16:53

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Julie Wolf

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16/4/2018 Can colistin resistance be reversed?

Julie Wolf is the ASM Science Communications Specialist. She contributes to the ASM social
media and blog network and hosts the Meet the Microbiologist podcast. She also runs
workshops at ASM conferences to help scientists improve their own communication skills.
Follow Julie on Twitter for more ASM and microbiology highlights at @JulieMarieWolf.
Julie earned her Ph.D. from the University of Minnesota, focusing on medical mycology and
infectious disease. Outside of her work at ASM, she maintains a strong commitment to scientific education and
teaches molecular biology at the community biolab, Genspace. She lives in beautiful New York City.

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bijaya muktan • 2 days ago

good work!! let's stop mcr gene on E. coli before it comes to be worldwide!!!
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