Intrinsic colistin resistance

Abstract

The global dissemination of colistin resistance has received a great deal of attention recently. The mechanism of colistin resistance can be generally classified as mcr-1-independent (intrinsic) or mcr-1-dependent (acquired). In The Lancet Infectious Diseases, Stefan Nicolet and colleagues1Nicolet S Goldenberger D Schwede T Page M Creus M Plasmid-mediated colistin resistance in a patient infected with Klebsiella pneumoniae.Lancet Infect Dis. 2016; 16: 998-999Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar presented a case in which a blood isolate of Klebsiella pneumoniae developed colistin resistance after receiving colistin treatment. Neither the mcr-1 gene nor any known mutations associated with colistin resistance were found in the genome, but an additional mcr-1-null plasmid was found to be acquired when it was compared with the parental susceptible isolate. The authors therefore concluded that colistin resistance was conferred by an unidentified determinant harboured by the acquired plasmid. Although this is a very interesting case, we think more evidence is necessary to support the conclusion. Extensive studies have identified that the intrinsic colistin resistance in K pneumoniae is mostly mediated by specific mutations in the two-component regulatory systems PmrAB and PhoPQ, as well as in the mgrB gene, resulting in modifications of the lipid A component of the lipopolysaccharide and a reduced negative charge on the outer membrane. However, few studies have found a correlation between the mutation-independent resistance mechanism and the overexpression of two-component regulatory systems in K pneumoniae. As recently shown by Hjort and colleagues,2Hjort K Nicoloff H Andersson DI Unstable tandem gene amplification generates heteroresistance (variation in resistance within a population) to colistin in Salmonella enterica.Mol Microbiol. 2016; (published online July 6.)https://doi.org/10.1111/mmi.13459Crossref PubMed Scopus (47) Google Scholar overexpression of PmrD alone in Salmonella Typhimurium is sufficient to confer colistin resistance. PmrD is involved in the regulation of the PmrAB system via binding to PmrA, leading to persistent expression of the PmrA-activated genes in S Typhimurium, in which it connects the PhoPQ and PmrAB systems. A similar regulation pattern is also found in K pneumoniae, but not in Escherichia coli and Enterobacter cloacae complex.3Guérin F Isnard C Sinel C et al.Cluster-dependent colistin-dependent colistin hetero-resistance in Enterobacter cloacae complex.J Antimicrob Chemother. 2016; (published online July 11.)https://doi.org/10.1093/jac/dkw260Crossref Scopus (54) Google Scholar Therefore, the expression level of lipopolysaccharide modification-related two-component regulatory systems and genes (eg, mgrB, lpxM, and waa) would be worth investigating in the two blood isolates. Additionally, capsular polysaccharides are thought to be involved in colistin resistance in K pneumoniae. Campos and colleagues4Campos MA Vargas MA Regueiro V Llompart CM Albertí S Bengoechea JA Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides.Infect Immun. 2004; 72: 7107-7114Crossref PubMed Scopus (328) Google Scholar revealed that the amount of capsular polysaccharide bound to the cell surface and the cps transcriptional level is greatly stimulated when exposed to polymyxin B, thus conferring resistance.4Campos MA Vargas MA Regueiro V Llompart CM Albertí S Bengoechea JA Capsule polysaccharide mediates bacterial resistance to antimicrobial peptides.Infect Immun. 2004; 72: 7107-7114Crossref PubMed Scopus (328) Google Scholar This finding is further supported by a study that, using atomic force microscopy, showed that the Young's modulus of the capsule was increased in a colistin-resistant K pneumoniae strain compared with that in a colistin-susceptible strain, which cannot be removed by colistin.5Formosa C Herold M Vidaillac C Duval RE Dague E Unravelling of a mechanism of resistance to colistin in Klebsiella pneumoniae using atomic force microscopy.J Antimicrob Chemother. 2015; 70: 2261-2270Crossref PubMed Scopus (41) Google Scholar Last, whether the colistin-resistant blood isolate was heteroresistant or had a homogenous resistance phenotype is unknown, since heteroresistance is more prevalent than stable colistin resistance in K pneumoniae in some instances,2Hjort K Nicoloff H Andersson DI Unstable tandem gene amplification generates heteroresistance (variation in resistance within a population) to colistin in Salmonella enterica.Mol Microbiol. 2016; (published online July 6.)https://doi.org/10.1111/mmi.13459Crossref PubMed Scopus (47) Google Scholar as well as in several clusters of the E cloacae complex.3Guérin F Isnard C Sinel C et al.Cluster-dependent colistin-dependent colistin hetero-resistance in Enterobacter cloacae complex.J Antimicrob Chemother. 2016; (published online July 11.)https://doi.org/10.1093/jac/dkw260Crossref Scopus (54) Google Scholar Such a phenotype could disrupt the results if more than a single colony on the medium with colistin was used for sequencing. We declare no competing interests. KZ and YX contributed equally. Plasmid-mediated colistin resistance in a patient infected with Klebsiella pneumoniaeIt is alarming that the plasmid-mediated mcr-1-encoded colistin resistance discovered by Yi-Yun Liu and colleagues,1 probably selected in cows and pigs as discussed by Marisa Haenni and colleagues2 and Surbhi Malhorta-Kumar and colleagues,3 is now spreading globally in Gram-negative pathogens.4 Moreover, colistin-resistant Escherichia coli without the canonical mcr-1 gene suggest that other (transferable) colistin-resistant mechanisms exist.3 Full-Text PDF