As the antibiotic resistance crisis worsens, the emergence of new antibiotic resistance genes is worrisome, even if it may no longer be surprising. The recently reported identification of mcr-9, a novel gene conferring resistance to the antibiotic colistin, raises unique concerns as colistin is one of the world’s few last-resort antibiotics.

The newly discovered gene, mcr-9, discovered by food scientists at Cornell University in Ithaca, New York, belongs to a class of plasmid-borne genes that confer resistance to colistin. To date, eight known mcr homologues have been described (mcr-1 to -8.) Laura Carroll, a PhD student at Cornell, found mcr-9 in Salmonella enterica serotype Typhimurium genome, while screening Salmonella genomes for antimicrobial resistance genes.

“This last-resort antibiotic has been designated a highest-priority antibiotic by the United Nations’ World Health Organization, and the mcr-9 gene causes bacteria to resist it,” said Martin Wiedmann PhD, professor in food safety at Cornell University and senior author on the study. “In treatments, if colistin does not work, it literally could mean death for patients.”

The paper entitled, “Identification of Novel Mobilized Colistin Resistance Gene mcr-9 in a Multidrug-Resistant, Colistin-Susceptible Salmonella enterica Serotype Typhimurium Isolate” is published in mBio.

The authors note that, until recently, bacterial resistance to colistin was thought to be acquired solely via chromosomal point mutations. That is until the plasmid-mediated colistin resistance gene mcr-1 was described in E. coli in 2015. Mcr-1 is a phosphoethanolamine transferase that modifies cell membrane lipid A head groups with a phosphoethanolamine residue, reducing affinity to colistin. In the last four years, seven additional mcr homologues (mcr-2 to -8) have been identified in Enterobacteriaceae. Mcr-9 is the latest in this new series of “mobilized colistin-resistance” genes. The amino acid sequence of mcr-9 most closely resembles mcr-3 and expression of mcr-9 conferred resistance to colistin in E. coli, albeit at a lower level than mcr-3. Pairwise comparisons of the predicted protein structures associated with all nine mcr homologues (Mcr-1 to -9) revealed that Mcr-9, Mcr-3, Mcr-4, and Mcr-7 share a high degree of similarity at the structural level.

Because of these results suggesting that mcr-9 is capable of conferring resistance to colistin, the authors write that it “should be immediately considered when monitoring plasmid-mediated colistin resistance.”

“Plasmid-borne mcr genes that confer resistance to colistin pose a threat to public health at an international scale, as they can be transmitted via horizontal gene transfer and have the potential to spread globally,” the authors wrote.

Colistin is a last-resort antibiotic that is used to treat severe infections caused by MDR and extensively drug-resistant (XDR) bacteria. The World Health Organization (WHO) has designated colistin as a “highest priority critically important antimicrobial for human medicine,” as it is often one of the only therapies available for treating serious bacterial infections in critically ill patients.

“If you go to a hospital and this gene is floating around, that can be trouble. The gene is moveable. It jumps,” Wiedmann said. “In a hospital setting, being able to screen a patient for resistance allows doctors and nurses to isolate the patient and maintain biosecurity.”

Therefore, the establishment of a complete reference of mcr genes that can be used to screen for plasmid-mediated colistin resistance is essential for developing effective control strategies.

 

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