Abstract
Over-expression of AdeABC efflux pump stimulated continuously by the mutated AdeRS two component system has been found to result in antimicrobial resistance, even tigecycline (TGC) resistance, in multidrug-resistant Acinetobacter baumannii (MRAB). Although the insertion sequence, ISAba1, contributes to one of the AdeRS mutations, the detail mechanism remains unclear. In the present study we collected 130 TGC-resistant isolates from 317 carbapenem resistant MRAB (MRAB-C) isolates, and 38 of them were characterized with ISAba1 insertion in the adeS gene. The relationship between the expression of AdeABC efflux pump and TGC resistant was verified indirectly by successfully reducing TGC resistance with NMP, an efflux pump inhibitor. Further analysis showed that the remaining gene following the ISAba1 insertion was still transcribed to generate a truncated AdeS protein by the Pout promoter on ISAba1 instead of frame shift or pre-termination. Through introducing a series of recombinant adeRS constructs into a adeRS knockout strain, we demonstrated the truncated AdeS protein was constitutively produced and stimulating the expression of AdeABC efflux pump via interaction with AdeR. Our findings suggest a mechanism of antimicrobial resistance induced by an aberrant cytoplasmic sensor derived from an insertion element.
Highlights
Acinetobacter baumannii, a Gram-negative coccobacillus usually found in soil and water, has emerged as a highly problematic nosocomial pathogen [1]
Antimicrobial susceptibility testing revealed that the 317 clinical multidrug-resistant Acinetobacter baumannii (MRAB)-C isolates were resistant to all antibiotics tested in the Vitek-2 system
To verify the effect of AdeABC efflux pump on TGC resistance, all MRAB-C isolates were tested for their MIC of TGC in the presence of NMP, an efflux pump inhibitor (Figure 1B)
Summary
Acinetobacter baumannii, a Gram-negative coccobacillus usually found in soil and water, has emerged as a highly problematic nosocomial pathogen [1]. The expression of AdeABC efflux pump is tightly regulated by the two-component system which contains a sensor kinase (SK) AdeS and a response regulator (RR) AdeR, encoded by the adeRS operon. Some of the IS elements contain promoters which can enhance the expression of their downstream antibiotic resistance genes [22]. Previous studies found that ISAba insertion mutation within the adeS gene can enhance overexpression of the AdeABC efflux pump system and cause TGC resistant [9]. We investigated the prevalence, genotype, AdeABC efflux pump expression and TGC resistance pattern of MRAB-C clinical isolates in which adeRS operon was uniquely destroyed by insertion of an IS element. The truncated AdeS protein was responsible for enhancing AdeABC efflux pump overexpression
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