PDF(Pubmed)
Abstract：
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.
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.
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.
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.
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.
摘要：
阴沟肠杆菌复合体（ECC）是一种常见的机会性病原体，可引起人类各种感染。由于其诱导型染色体AmpCβ-内酰胺酶（AmpC），ECC固有地对第一代和第二代头孢菌素具有抗性。然而,β-内酰胺类抗生素是否能增强ECC耐药性目前尚不清楚.
在这项研究中,我们发现，在阴沟肠杆菌（EC）中，头孢唑啉（CFZ）和亚胺培南（IMP）的亚抑制浓度（SIC）可以通过NagZ促进AmpC的表达并增强其对β-内酰胺的抗性。Further,响应于CFZ和IMP的SIC，AmpC在EC中表现出实质性的上调。在nagZ敲除EC(ΔnagZ)中，对β-内酰胺类抗生素的耐药性相当减弱，CFZ和IMP对AmpC诱导的影响完全消除。NagZ异位表达可以挽救CFZ和IMP对AmpC的诱导作用并增加ΔnagZ抗性。更重要的是,CFZ和IMP具有以NagZ依赖性方式诱导AmpR的靶基因表达的潜力。
我们的研究结果表明，NagZ是CFZ和IMP促进AmpC表达和抗性的关键决定因素，并且CFZ和IMP应谨慎使用，因为它们可能会加剧ECC抗性。同时,这项研究进一步加深了我们对ECC抗性机制的理解.
在这项研究中,我们发现，在阴沟肠杆菌（EC）中，头孢唑啉（CFZ）和亚胺培南（IMP）的亚抑制浓度（SIC）可以通过NagZ促进AmpC的表达并增强其对β-内酰胺的抗性。Further,响应于CFZ和IMP的SIC，AmpC在EC中表现出实质性的上调。在nagZ敲除EC(ΔnagZ)中，对β-内酰胺类抗生素的耐药性相当减弱，CFZ和IMP对AmpC诱导的影响完全消除。NagZ异位表达可以挽救CFZ和IMP对AmpC的诱导作用并增加ΔnagZ抗性。更重要的是,CFZ和IMP具有以NagZ依赖性方式诱导AmpR的靶基因表达的潜力。
我们的研究结果表明，NagZ是CFZ和IMP促进AmpC表达和抗性的关键决定因素，并且CFZ和IMP应谨慎使用，因为它们可能会加剧ECC抗性。同时,这项研究进一步加深了我们对ECC抗性机制的理解.
