Prevalence of insertion sequence elements in plasmids relating to mgrB gene disruption causing colistin resistance in Klebsiella pneumoniae

Abstract

Colistin is a last resort antibiotic for the treatment of carbapenemase producing Klebsiella pneumoniae. The disruption of the mgrB gene by insertion sequences (ISs) is a mechanism mediating colistin resistance. Plasmids encode mobilizable IS elements which integrate into the mgrB gene in K. pneumoniae causing gene inactivation and colistin resistance. The species prevalence of mgrB-gene disrupting insertion elements ISL3 (ISKpn25), IS5 (ISKpn26), ISKpn14, and IS903B present on plasmids were assessed. IS containing plasmids were also scanned for antimicrobial resistance genes, including carbapenem resistant genes.Plasmids encoding ISs are abundant in K. pneumoniae. IS903B was found in 28 unique Inc groups, while ISKpn25 was largely carried by IncFIB(pQil) plasmids.ISKpn26 and ISKpn14 were most often found associated with IncFII(pHN7A8) plasmids. Of the 34 unique countries which contained any of the IS elements, ISKpn25 was identified from 26. ISKpn26, ISKpn14, and IS903B ISs were identified from 89.3%, 44.9%, and 23.9% plasmid samples from China. Plasmids carrying ISKpn25, ISKpn14, and ISKpn26 IS have a 4.6-, 6.0-, and 6.6-fold higher carbapenemase gene count, respectively, relative to IS903B-carrying plasmids. IS903B bearing plasmids have a 20-, 5-, and 5-fold higher environmental source isolation count relative to ISKpn25, ISKpn14, and ISKpn26 bearing plasmids. ISKpn25 present on IncFIB(pQil) sourced from clinical settings is established across multiple countries, while ISKpn26, ISKpn14, and IS903B appear most often in China. Carbapenemase presence in tandem with IS elements may help promote an extensively drug resistant profile in K. pneumoniae limiting already narrow treatment options.

Genetic Diversity of Polymyxin-Resistance Mechanisms in Clinical Isolates of Carbapenem-Resistant Klebsiella pneumoniae: a Multicenter Study in China

“…IS-medicated insertion was the main reason for mgrB inactivation (65.38% in this study). Furthermore, the IS types involved IS kpn14 (52.94%), followed by IS 903 (23.53%,), IS kpn26 (11.76%), and IS kpn18 (11.76%), consistent with previous reports ( 16 , 18 , 38 , 39 ). IS kpn14 was prevalent as the main mgrB -inserted type in our study, which might vary geographically, such as IS 5 -like in Italy and Switzerland ( 4 , 37 ) and IS kpn26 in Taiwan ( 16 ).…”

Characterization of Carbapenemase-Producing Klebsiella pneumoniae Isolates from Two Romanian Hospitals Co-Presenting Resistance and Heteroresistance to Colistin

“…Mutation of mgrB gene was the basis for resistance most frequently encountered in our study (11 out of the total strains) and was induced by either ISKpn25 (n = 6), ISKpn26 (n = 1), or a missense mutation M27K (n = 4), predicted as deleterious by bioinformatics tools. Several recent studies have highlighted the pivotal role of ISs in contributing to the emergence of colistin resistance by disrupting the mgrB gene [ 19 , 20 , 21 , 30 , 31 , 32 ]. Our findings provide evidence that plasmid IncFIB(pQil) encodes ISkpn25, while the ISKpn26 element is associated with IncFIA(HI1) and IncR plasmids.…”

“…Our findings provide evidence that plasmid IncFIB(pQil) encodes ISkpn25, while the ISKpn26 element is associated with IncFIA(HI1) and IncR plasmids. Fordham et al demonstrated similar connections between these IS elements and their companion plasmid families, with the exception of the relationship between ISKpn26 and IncFII(pHN7A8) plasmids [ 19 ]. The M27K mutation in the mgrB gene was also reported to mediate colistin resistance in a previous study [ 52 ].…”

“…A panel of various genes modulates these modifications, essentially based on the two-component regulatory systems (TCRSs) phoPQ and pmrAB and the feedback regulator mgrB gene and the colistin resistance regulation ( crrAB ) operon, respectively [ 17 , 18 ]. Transposition of insertion sequences (ISs) such as ISL3 (ISKpn25), IS5 (ISKpn26), ISKpn14, and IS903B from plasmids into the mgrB gene mediates the inactivation and disruption of this regulator gene, conferring colistin resistance [ 19 , 20 , 21 ]. Antibiotic heteroresistance is considered to be the presence of subpopulations with increased resistance within the majority cell population in the same culture [ 22 ].…”

MgrB mutations causing colistin resistance in ST11 and ST15 Klebsiella pneumoniaes in a tertiary teaching hospital in China

“…Inactivation of mgrB gene has been reported that leads to upgrade of the PhoP-PhoQ, which make for overexpression of the relevant operon and resistance to colistin [6]. At the same time, mutations in the above regulatory systems (pmrA, pmrB, pmrC, crrAB, mgrB and phoP/phoQ) have also been shown to be associated with colistin resistance [7].…”