Friday, 23 June 2017 15:21

ESKAPE pathogens expressing mcr-1 have varying colistin resistance phenotypes

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Published in mBiosphere

The gene that confers colistin resistance, mcr-1, has been found in more countries, animals and animal products, and in more hospital settings than was originally thought when the first plasmid-borne allele was reported eighteen months ago. The gene was found in both Escherichia coli and Klebsiella pneumoniae isolates, and both of these species are members of the ESKAPE pathogen group – but does the mcr-1 gene expression lead to the same phenotype in other ESKAPE pathogens? A new Antimicrobial Agents and Chemotherapy report suggests that mcr-1 expression may not correlate with similar levels of colistin resistance across all of the ESKAPE pathogen members.

AACJournal: Structural Modification of Lipopolysaccharide Conferred by mcr-1 in Gram-Negative ESKAPE Pathogens

The mcr-1 gene encodes an enzyme (specifically, phosphoethanolamine, or PEtN, transferase) that modifies the structure of the lipopolysaccharide (LPS) that composes the outermost layer of the gram-negative cell envelope. This modification decreases the overall negative charge of the bacterial cell surface, and decreases the attraction between the negatively-charged LPS and positively-charged colistin. A team of scientists including first author Yi-Yun Liu and senior scientist Yohei Doi asked whether the same allele, if expressed in other ESKAPE pathogens, would also confer colistin resistance.

colistin resistance tableAddition of mcr-1 increased resistance in all ESKAPE pathogens tested. Source.

To do this, the scientific team transformed four different bacterial species with mcr-1: E. coli, K. pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa (the other members, Enterococcus species and Staphylococcus aureus, are gram positive and don’t contain LPS as part of their cell envelope). All species increased in colistin resistance when carrying mcr-1, but the level of resistance varied. While E. coli, K. pneumoniae, and A. baumannii could tolerate at least 16 times (and often, higher) the colistin concentration when carrying mcr-1, P. aeruginosa could only tolerate up to 4 times as much (see table, right). The phenotype (colistin resistance) was the same but varied in its strength between species. Why?

The scientists turned to LPS to answer this question. Mass spectrometry of LPS from each mcr-1 transformed strain confirmed that mcr-1 act as a PEtN transferase in all species, including easily detectable PEtN-modified LPS in P. aeruginosa. Another possible explanation for variable resistance could be differences in mcr-1 expression levels between species: The native promoter of the mcr-1 cassette tested in this study may have resulted in different levels of mcr-1 expression in each species (the scientists didn’t look at expression levels). If this is the case, future genetic recombinations could result in species-specific promoters that confer higher expression, and higher levels of resistance. 

The researchers show that mcr-1 increases colistin resistance in all gram-negative bacteria tested, but that the level of increased resistance varies among each species. The clinical implications of this study are due to colistin’s role as one of the antibacterial drugs of last resort, meaning colistin is used after other drugs have failed. Although mcr-1 hasn’t been detected in all of the ESKAPE pathogens tested here, the plasmid-encoded nature of the resistance cassette suggests it may be shared via horizontal gene transfer. These various levels of resistance are important to consider in surveillance for colistin-resistant isolates, and may require more stringent detection methods than detection of the mcr-1 gene alone.

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Last modified on Friday, 23 June 2017 15:56
Julie Wolf

ASM Communications Social Media Specialist Julie Wolf spent her research career focused on medical mycology and infectious disease. Broadly interested in microbiology and scientific communication, she has taught at Long Island University and the community biolab Genspace and has written for the Scientista Foundation and Scholastic’s Science World magazine. Follow her on Twitter for more ASM and Microbiology highlights at @JulieMarieWolf.