title: Gene expression analysis of two extensively drug-resistant tuberculosis isolates show that two-component response systems enhance drug resistance.
abstract: Global analysis of expression profiles using DNA microarrays was performed between a reference strain H37Rv and two clinical extensively drug-resistant isolates in response to three anti-tuberculosis drug exposures (isoniazid, capreomycin, and rifampicin). A deep analysis was then conducted using a combination of genome sequences of the resistant isolates, resistance information, and related public microarray data. Certain known resistance-associated gene sets were significantly overrepresented in upregulated genes in the resistant isolates relative to that observed in H37Rv, which suggested a link between resistance and expression levels of particular genes. In addition, isoniazid and capreomycin response genes, but not rifampicin, either obtained from published works or our data, were highly consistent with the differentially expressed genes of resistant isolates compared to those of H37Rv, indicating a strong association between drug resistance of the isolates and genes differentially regulated by isoniazid and capreomycin exposures. Based on these results, 92 genes of the studied isolates were identified as candidate resistance genes, 10 of which are known resistance-related genes. Regulatory network analysis of candidate resistance genes using published networks and literature mining showed that three two-component regulatory systems and regulator CRP play significant roles in the resistance of the isolates by mediating the production of essential envelope components. Finally, drug sensitivity testing indicated strong correlations between expression levels of these regulatory genes and sensitivity to multiple anti-tuberculosis drugs in Mycobacterium tuberculosis. These findings may provide novel insights into the mechanism underlying the emergence and development of drug resistance in resistant tuberculosis isolates and useful clues for further studies on this issue.
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors: Guohua
authors: G
authors: Yu
authors: Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Medical School, Tongji University, Shanghai 200433, PR China.
authors: Zhenling
authors: Z
authors: Cui
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors: Xian
authors: X
authors: Sun
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors: Jinfu
authors: J
authors: Peng
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors: Jun
authors: J
authors: Jiang
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors: Wei
authors: W
authors: Wu
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors: Wenhua
authors: W
authors: Huang
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors: Kaili
authors: K
authors: Chu
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China.
authors: Lu
authors: L
authors: Zhang
authors: Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Medical School, Tongji University, Shanghai 200433, PR China. Electronic address: baoxue_ge@tongji.edu.cn.
authors: Baoxue
authors: B
authors: Ge
authors: State Key Lab of Genetic Engineering, Shanghai Engineering Research Center of Industrial Microorganisms, College of Life Sciences, Fudan University, Shanghai 200433, PR China. Electronic address: yaoli@fudan.edu.cn.
authors: Yao
authors: Y
authors: Li
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use; D019295:Computational Biology; D004269:DNA, Bacterial / Q000235:genetics* / Q000302:isolation & purification; D030541:Databases, Genetic; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics*; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy / Q000382:microbiology*; D020869:Gene Expression Profiling / Q000379:methods; D015964:Gene Expression Regulation, Bacterial; D053263:Gene Regulatory Networks; D005838:Genotype; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype
chemical_list: D000995:Antitubercular Agents; D004269:DNA, Bacterial
keywords: Drug resistance; Drug response; Extensively drug-resistant isolates; Regulatory network analysis; Two-component response systems