MgrB Inactivation Is Responsible for Acquired Resistance to Colistin in Enterobacter hormaechei subsp. steigerwaltii

Abstract

Multidrug-resistant strains belonging to the Enterobacter cloacae complex (ECC) group, and especially those belonging to clusters C-III, C-IV, and C-VIII, have increasingly emerged as a leading cause of health care-associated infections, with colistin used as one of the last lines of treatment. However, colistin-resistant ECC strains have emerged. The aim of this study was to prove that MgrB, the negative regulator of the PhoP/PhoQ two-component regulatory system, is involved in colistin resistance in ECC of cluster C-VIII, formerly referred to as Enterobacter hormaechei subsp. steigerwaltii. An in vitro mutant (Eh22-Mut) was selected from a clinical isolate of Eh22. The sequencing analysis of its mgrB gene showed the presence of one nucleotide deletion leading to the formation of a truncated protein of six instead of 47 amino acids. The wild-type mgrB gene from Eh22 and that of a clinical strain of Klebsiella pneumoniae used as controls were cloned, and the corresponding recombinant plasmids were used for complementation assays. The results showed a fully restored susceptibility to colistin and confirmed for the first time that mgrB gene expression plays a key role in acquired resistance to colistin in ECC strains.

Molecular mechanisms and clonal lineages of colistin-resistant bacteria across the African continent: a scoping review

“…steigerwaltii strain was isolated from urine samples of patients in a regional hospital in Djerba Island, southeastern Tunisia (Mhaya et al . 2020).…”

“…Deletion in the mgrB gene resulted in the formation of a truncated protein of six amino acids rather than the typical 47, identified in a colistin-resistant E. hormaechei subsp. steigerwaltii strain was isolated from urine samples of patients in a regional hospital in Djerba Island, southeastern Tunisia (Mhaya et al 2020).…”

Genetic Diversity of Virulent Polymyxin-Resistant Klebsiella aerogenes Isolated from Intensive Care Units

“…Studies have suggested that alterations in mgrB and pmrAB may be responsible for polymyxin resistance in Gram-negative pathogens [ 13 , 29 , 30 , 31 ]. The inactivation of mgrB , which encodes a negative feedback regulator of the PhoQ-PhoP signaling system, was recently demonstrated to be a common mutational mechanism responsible for acquired polymyxin resistance among the clinical isolates of K. pneumoniae , Enterobacter spp., and E. coli [ 14 , 15 , 21 , 32 , 33 , 34 , 35 ]. Mutations in mgrB may be the main determinant for colistin resistance in K. aerogenes [ 19 ].…”

“…Various studies have investigated the mechanisms associated with polymyxin-resistance in Gram-negative infections. The polymyxin exposure may triggered the genetic events that lead to gene modifications in the polymyxin-resistant isolates [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. However, studies on polymyxin-resistant Enterobacter spp.…”

Absence of mgrB Alleviates Negative Growth Effects of Colistin Resistance in Enterobacter cloacae

“…In contrast, the inactivation of mgrB is a known mechanism of fitness cost-free colistin resistance in K. pneumoniae, although the reason it does not exert a fitness cost is unknown [ 16 ]. Mutations within mgrB leading to colistin resistance have very recently been described in Enterobacter species, but the effect these mutations have on the growth rate has not been interrogated [ 18 , 19 ].…”