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Imipenem Treatment Induces Expression of Important Genes and Phenotypes in a Resistant Acinetobacter baumannii Isolate.

ABSTRACT: Acinetobacter baumannii has emerged as a notorious multidrug-resistant pathogen, and development of novel control measures is of the utmost importance. Understanding the factors that play a role in drug resistance may contribute to the identification of novel therapeutic targets. Pili are essential for A. baumannii adherence to and biofilm formation on abiotic surfaces as well as virulence. In the present study, we found that biofilm formation was significantly induced in an imipenem-resistant (Imp(r)) strain treated with a subinhibitory concentration of antibiotic compared to that in an untreated control and an imipenem-susceptible (Imp(s)) isolate. Using microarray and quantitative PCR analyses, we observed that several genes responsible for the synthesis of type IV pili were significantly upregulated in the Imp(r) but not in the Imp(s) isolate. Notably, this finding is corroborated by an increase in the motility of the Imp(r) strain. Our results suggest that the ability to overproduce colonization factors in response to imipenem treatment confers biological advantage to A. baumannii and may contribute to clinical success.

SUBMITTER: Dhabaan GN

PROVIDER: S-EPMC4775920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Carbapenem-resistance in Acinetobacter baumannii has gradually become a global challenge. To identify the genes involved in carbapenem resistance in A. baumannii, the transcriptomic responses of the completely sequenced strain ATCC 17978 selected with 0.5 mg/L (IPM-2 m) and 2 mg/L (IPM-8 m) imipenem were investigated using RNA-sequencing to identify differences in the gene expression patterns. RESULTS: A total of 88 and 68 genes were differentially expressed in response to IPM-2 m and IPM-8 m selection, respectively. Among the expressed genes, 50 genes were highly expressed in IPM-2 m, 30 genes were highly expressed in IPM-8 m, and 38 genes were expressed common in both strains. Six groups of genes were simultaneously expressed in IPM-2 m and IPM-8 m mutants. The three gene groups involved in DNA recombination were up-regulated, including recombinase, transposase and DNA repair, and beta-lactamase OXA-95 and homologous recombination. The remaining gene groups involved in biofilm formation were down-regulated, including quorum sensing, secretion systems, and the csu operon. The antibiotic resistance determinants, including RND efflux transporters and multidrug resistance pumps, were over-expressed in response to IPM-2 m selection, followed by a decrease in response to IPM-8 m selection. Among the genes over-expressed in both strains, blaOXA-95, previously clustered with the blaOXA-51-like family, showed 14-fold (IPM-2 m) to 330-fold (IPM-8 m) over-expression. The expression of blaOXA-95 in IPM-2 m and IPM-8 m cells was positively correlated with the rate of imipenem hydrolysis, as demonstrated through Liquid Chromatography-Mass Spectrometry/Mass Spectrometry, suggesting that blaOXA-95 plays a critical role in conferring carbapenem resistance. In addition, A. baumannii shows an inverse relationship between carbapenem resistance and biofilm production. CONCLUSION: Gene recombination and blaOXA-95 play critical roles in carbapenem resistance in A. baumannii. Taken together, the results of the present study provide a foundation for future studies of the network systems associated with carbapenem resistance.

Project description:Acinetobacter baumannii is an opportunistic gram-negative bacteria typically attributed to hospital-associated infection. It could also become multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan drug-resistant (PDR) during a short period. Although A. baumannii has been documented extensively, complete knowledge on the antibiotic-resistant mechanisms and virulence factors responsible for pathogenesis has not been entirely elucidated. This study investigated the drug resistance pattern and characterized the genomic sequence by de novo assembly of PDR A. baumannii strain VJR422, which was isolated from a catheter-sputum specimen. The results showed that the VJR422 strain was resistant to any existing antibiotics. Based on de novo assembly, whole-genome sequences showed a total genome size of 3,924,675-bp. In silico and conventional MLST analysis of sequence type (ST) of this strain was new ST by Oxford MLST scheme and designated as ST1890. Moreover, we found 10,915 genes that could be classified into 45 categories by Gene Ontology (GO) analysis. There were 1,687 genes mapped to 34 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The statistics from Clusters of Orthologous Genes (COG) annotation identified 3,189 genes of the VJR422 strain. Regarding the existence of virulence factors, a total of 59 virulence factors were identified in the genome of the VJR422 strain by virulence factors of pathogenic bacteria databases (VFDB). The drug-resistant genes were investigated by searching in the Comprehensive Antibiotic Resistance Database (CARD). The strain harbored antibiotic-resistant genes responsible for aminoglycoside, β-lactam-ring-containing drugs, erythromycin, and streptogramin resistance. We also identified resistance-nodulation-cell division (RND) and the major facilitator superfamily (MFS) associated with the antibiotic efflux pump. Overall, this study focused on A. baumannii strain VJR422 at the genomic level data, i.e., GO, COG, and KEGG. The antibiotic-resistant genotype and phenotype as well as the presence of potential virulence associated factors were investigated.

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Imipenem Treatment Induces Expression of Important Genes and Phenotypes in a Resistant Acinetobacter baumannii Isolate.

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