Abstract
Tuberculosis, caused by the pathogen Mycobacterium tuberculosis, is a worldwide public health threat. Mycobacterium tuberculosis is capable of resisting various stresses in host cells, including high levels of ROS and copper ions. To better understand the resistance mechanisms of mycobacteria to copper, we generated a copper-resistant strain of Mycobacterium smegmatis, mc2155-Cu from the selection of copper sulfate treated-bacteria. The mc2155-Cu strain has a 5-fold higher resistance to copper sulfate and a 2-fold higher resistance to isoniazid (INH) than its parental strain mc2155, respectively. Quantitative proteomics was carried out to find differentially expressed proteins between mc2155 and mc2155-Cu. Among 345 differentially expressed proteins, copper-translocating P-type ATPase was up-regulated, while all other ABC transporters were down-regulated in mc2155-Cu, suggesting copper-translocating P-type ATPase plays a crucial role in copper resistance. Results also indicated that the down-regulation of metabolic enzymes and decreases in cellular NAD, FAD, mycothiol, and glutamine levels in mc2155-Cu were responsible for its slowing growth rate as compared to mc2155. Down-regulation of KatG2 expression in both protein and mRNA levels indicates the co-evolution of copper and INH resistance in copper resistance bacteria, and provides new evidence to understanding of the molecular mechanisms of survival of mycobacteria under stress conditions.
Highlights
The ancient pathogen Mycobacterium tuberculosis causes tuberculosis (TB) in one third of the world’s population and is one of the formidable threats to human health [1]
On the basis of quantitative proteomic analysis, we showed that the increased copper and INH resistance in mc2155-Cu was resulted from the up-regulation of copper-translocating P-type ATPase expression and the down-regulation of KatG2 expression
Decreases in NAD and glutamine levels and down-regulation of oxidoreductases in mc2155-Cu contribute to its slow growth rate as compared to mc2155
Summary
The ancient pathogen Mycobacterium tuberculosis causes tuberculosis (TB) in one third of the world’s population and is one of the formidable threats to human health [1]. M. tuberculosis is capable of resisting survival stresses and stays alive in host cells for years that causes the prevalence of TB. The IFN-γ–mediated activation of macrophages is the major immune response of the host cells to M. tuberculosis infection, in which M. tuberculosis residing in phagosomes was cleared by a range of hydrolytic enzymes, PLOS ONE | DOI:10.1371/journal.pone.0127788. Proteomic Analysis of Drug-Resistant Mycobacteria bactericidal peptides, and reactive oxygen and nitrogen intermediates in phagolysosome [5,6]. Recent studies have demonstrated that copper ions in host cells possess bactericidal effects against invading mycobacteria [7,8]
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