Zinc stress induces copper depletion in Acinetobacter baumannii

Abstract

BackgroundThe first row transition metal ions zinc and copper are essential to the survival of many organisms, although in excess these ions are associated with significant toxicity. Here, we examined the impact of zinc and copper stress on Acinetobacter baumannii, a common opportunistic pathogen.ResultsWe show that extracellular zinc stress induces a copper-specific depletion phenotype in A. baumannii ATCC 17978. Supplementation with copper not only fails to rescue this phenotype, but further exacerbates the copper depletion. Extensive analysis of the A. baumannii ATCC 17978 genome identified 13 putative zinc/copper resistance efflux pumps. Transcriptional analyses show that four of these transporters are responsive to zinc stress, five to copper stress and seven to the combination of zinc and copper stress, thereby revealing a likely foundation for the zinc-induced copper starvation in A. baumannii. In addition, we show that zinc and copper play crucial roles in management of oxidative stress and the membrane composition of A. baumannii. Further, we reveal that zinc and copper play distinct roles in macrophage-mediated killing of this pathogen.ConclusionsCollectively, this study supports the targeting of metal ion homeostatic mechanisms as an effective antimicrobial strategy against multi-drug resistant bacterial pathogens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-017-0965-y) contains supplementary material, which is available to authorized users.

Essential Gene Clusters Involved in Copper Tolerance Identified in Acinetobacter baumannii Clinical and Environmental Isolates

“…As reported by previous studies, putative copper-related genes were located on chromosomal regions of A. baumannii [11][12][13]. To identify and localize copper-related genes, we sequenced the genome of A. baumannii AB003 and found fourteen copper-related genes located in four chromosomal regions (clusters A, B, C, and D).…”

“…A. baumannii normally inhabits water and soil, and has also been isolated from hospital environments [9,10]. This bacterium is capable of growing in a wide range of diverse environmental conditions and the genes involved in copper tolerance have been identified and characterized in clinical isolates [11][12][13][14]. Williams et al [11] observed that A. baumannii harbored many putative copper-related genes located on chromosomal regions, while a comparative genome study revealed the region carrying cop genes of A. baumannii were found to be embedded on genomic islands (GEIs), namely G08 and G62 [15].…”

“…Williams et al [11] observed that A. baumannii harbored many putative copper-related genes located on chromosomal regions, while a comparative genome study revealed the region carrying cop genes of A. baumannii were found to be embedded on genomic islands (GEIs), namely G08 and G62 [15]. Previous studies reported that exposure of A. baumannii cells to copper caused overexpressions of the genes encoding the putative copper transporters (actP1, actP2, and copB), the putative copper regulator (copR) and the putative copper-binding proteins (copD and ABUW_2708) [11,12]. Recently, a functional analysis by Alquethamy et al [14] showed that the copper efflux P-type ATPases mediates copper tolerance, and interestingly, this efflux pump also contributes to A. baumannii survival in a pneumonia murine model [14].…”

“…Recently, a functional analysis by Alquethamy et al [14] showed that the copper efflux P-type ATPases mediates copper tolerance, and interestingly, this efflux pump also contributes to A. baumannii survival in a pneumonia murine model [14]. These supported that copper tolerance is essential for both cellular responses to copper toxicity and virulence of A. baumannii, whereas, the mechanism of copper tolerance in A. baumannii has only been studied in a limited number of isolates [11][12][13]. This study aims to examine phenotypic and genotypic tolerance to copper in a large collection of A. baumannii from both clinical and environmental origins, and to investigate the genotypic response to copper tolerance in a representative clinical A. baumannii isolate.…”

Responses of Acidithiobacillus thiooxidans A01 to Individual and Joint Nickel (Ni2+) and Ferric (Fe3+)

“…Similarly, extracellular zinc acted in a dose dependent manner to competitively inhibit manganese uptake by Streptococcus pneumonia [43]. Zinc stress induces copper depletion in Acinetobacter baumannii [44]. The ABC transport system is another basic defense against heavy metals [45].…”