Cefazolin and imipenem enhance AmpC expression and resistance in NagZ-dependent manner in Enterobacter cloacae complex

Abstract

Background Enterobacter cloacae complex (ECC) is a common opportunistic pathogen and is responsible for causing various infections in humans. Owing to its inducible chromosomal AmpC β-lactamase (AmpC), ECC is inherently resistant to the 1st- and 2nd- generation cephalosporins. However, whether β-lactams antibiotics enhance ECC resistance remains unclear. Results In this study, we found that subinhibitory concentrations (SICs) of cefazolin (CFZ) and imipenem (IMP) can advance the expression of AmpC and enhance its resistance towards β-lactams through NagZ in Enterobacter cloacae (EC). Further, AmpC manifested a substantial upregulation in EC in response to SICs of CFZ and IMP. In nagZ knockout EC (ΔnagZ), the resistance to β-lactam antibiotics was rather weakened and the effect of CFZ and IMP on AmpC induction was completely abrogated. NagZ ectopic expression can rescue the induction effects of CFZ and IMP on AmpC and increase ΔnagZ resistance. More importantly, CFZ and IMP have the potential to induce the expression of AmpR's target genes in a NagZ-dependent manner. Conclusions Our findings suggest that NagZ is a critical determinant for CFZ and IMP to promote AmpC expression and resistance and that CFZ and IMP should be used with caution since they may aggravate ECC resistance. At the same time, this study further improves our understanding of resistance mechanisms in ECC.

Filling knowledge gaps related to AmpC-dependent β-lactam resistance in Enterobacter cloacae

“…Although AmpC hyperproduction-based β-lactam resistance has been deeply studied in E. cloacae from almost all perspectives 21 , 22 , 25 , 31 , 58 , 59 , 61 – 63 , its potentially associated biological cost has never been quantified, which constrasts with awide array of β-lactamases, properly characterized in this sense 14 , 43 , 45 . Cloning AmpC in a multicopy plasmid (previous section) enabled us to measure the direct impact of hyperproducing an instrinsic β-lactamase in a similar way as that for acquired enzymes, which usually show constitutive high expression thanks to strong promoters 64 , 65 .…”

“…A very important body of information is available concerning the chromosomal AmpC of E. cloacae 4 , 17 – 21 , 63 . However, there are still some knowledge gaps on the topic that we wanted to fill, given the relevance of this ESKAPE pathogen and this resistance mechanism 2 , 4 .…”

Cefepime versus carbapenems for treatment of AmpC beta-lactamase-producing Enterobacterales bloodstream infections

“…Notably, emergence of resistance of AmpC-PE was more commonly noted after treatment of the initial infection episode with carbapenems. Recently, imipenem has been shown to promote AmpC expression and may induce an adaptive response to carbapenems by regulating key genes involved in the control of efflux pumps and porins, which could lead to a multidrug-resistant profile in clinical isolates, contributing to possible treatment failure [ 24 , 25 ]. Further studies are needed to compare the potential of different beta-lactams in inducing resistance by induction of AmpC or other resistance mechanisms, such as the up-regulation of efflux pumps or down-regulation of the expression of porins.…”