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Differential gene expression in mouse kidney following 72 hours of colistin exposure by Illumina WG-6_V2 array

ABSTRACT: Colistin sulfate (polymixin E) is an antibiotic prescribed with resurging frequency for multidrug resistant gram negative bacterial infections. It is associated with nephrotoxicity in humans in up to 33% of cases. Little is known regarding genes involved in colistin nephrotoxicity. A murine model of colistin-mediated kidney injury was developed. C57/BL6 mice were administered saline or colistin at a dose of 16mg/kg/day in 2 divided doses. An Illumina gene expression array was performed on kidney RNA harvested 72 hours after first colistin dose to identify differentially expressed genes early in drug treatment. Array platform was MouseWG-6, 48,000 probes. Drug given intraperitoneal.

ORGANISM(S): Mus musculus

PROVIDER: GSE46410 | GEO | 2013/11/05

SECONDARY ACCESSION(S): PRJNA200297

REPOSITORIES: GEO

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Project description:Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common modes of action which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89% common genes for colistin B), though effects on gene expression were generally lower (0-1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed the effects were driven by colistin and included disturbances in fatty acid synthesis and catabolism and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72% of DEGs shared with monotherapy, resulting in substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients. Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common modes of action which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89% common genes for colistin B), though effects on gene expression were generally lower (0-1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed the effects were driven by colistin and included disturbances in fatty acid synthesis and catabolism and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72% of DEGs shared with monotherapy, resulting in substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients.

Project description:Cephaloridine (CER) is a classical beta-lactam antibiotic that has long served as a model drug for the study of cephalosporin antibiotic-induced acute tubular necrosis. In the present study, we analyzed gene expression profiles in the kidney of rats given subtoxic and toxic doses of CER in order to identify gene expression alterations closely associated with CER-induced nephrotoxicity. Male Fisher 344 rats were intravenously injected with three different doses (150, 300, and 600 mg/kg) of CER, and sacrificed after 24 h. Only the high dose (600 mg/kg) caused mild proximal tubular necrosis and a slight renal dysfunction. Microarray analysis identified hundreds of genes differentially expressed in the renal cortex following the exposure to CER, which could be classified into two main groups that were deregulated in dose-dependent and high dose-specific manners. The genes upregulated dose-dependently mainly included those involved in detoxification and antioxidant defense, which was considered to be associated with CER-induced oxidative stress. In contrast, the genes showing high dose-specific (lesion-specific) induction included a number of genes related to cell proliferation, which appeared to reflect a compensatory response to CER injury. We also found a subset of G2/M phase genes that exhibited hormesis-like (U-Shape) biphasic dose response; namely, downregulation only at the low and/or middle (subtoxic) doses. Furthermore, we could predict potential transcription regulators responsible for the observed gene expression alterations, such as Nrf2 and E2F family. Among the candidate gene biomarkers, kidney injury molecule 1 was markedly upregulated at the mildly toxic dose, suggesting that this gene can be used as an early and sensitive indicator for cephalosporin nephrotoxicity. In conclusion, our transcriptomic data revealed several characteristic expression patterns of genes associated with specific cellular processes, including oxidative stress response and proliferative response, upon exposure to CER, which may enhance our understandings of molecular mechanisms behind cephalosporin antibiotic-induced nephrotoxicity. Keywords: compound treatment, dose response In the present study, we acquired gene expression profiles in the kidney of rats given subtoxic and toxic doses of cephaloridine (CER) using whole-genome oligonucleotide microarrays. Male rats were injected with vehicle alone and three different doses (150, 300, and 600 mg/kg) of CER, and sacrificed after 24 h. Each dose group contained 3 animals.

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Differential gene expression in mouse kidney following 72 hours of colistin exposure by Illumina WG-6_V2 array

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