MCR-3 and MCR-9 confer species-specific increases in colistin MICs

For the clinical treatment of infections with Enterobacteriaceae , the development of resistance to last-resort antimicrobials like colistin is of concern, as it limits treatment options. Since 2015, ten families of mobile colistin resistance ( mcr ) genes have been discovered; however, our understanding of MCR remains limited because (i) mcr-1 is the most studied variant, (ii) mcr variants are rarely compared and (iii) mcr variants are primarily studied in Escherichia coli , even though studies have shown that mcr variants can confer significantly different phenotypes and that lipid A (i.e. the target of colistin and mcr- modification) structurally differs between bacterial species. To fill this gap, we examined how mcr-3 and mcr-9 , as two less frequently studied mcr variants, impact the colistin resistance of laboratory-adapted and real-world (i.e. clinical or food) isolates of E. coli , Salmonella enterica and Klebsiella pneumoniae . We found that while mcr-3 consistently conferred colistin resistance to all tested strains, mcr-9 only conferred resistance to two strains. The fold-change in colistin minimum inhibitory concentrations was significantly impacted by both the bacterial species and the mcr variant but not by whether a strain was a laboratory-adapted or real-world isolate. Overall, our results suggest that while laboratory-adapted strains may provide a good estimate of mcr -mediated colistin resistance of real-world isolates, findings of mcr -mediated phenotypes in one bacterial species should not be extrapolated to another.