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Disulfiram inhibits bacterial growth by inducing zinc-dependent reactive oxygen species

ABSTRACT: With the growing threat posed by emerging drug-resistant bacteria, the discovery of new antibiotics and the exploration of additional antimicrobial mechanisms of medicines currently used in the clinic are urgent. In this study, we found that disulfiram, a drug used for the treatment of alcohol addiction, inhibited the growth of multiple bacteria and quickly inhibited the growth of E. coli. When combined with kanamycin or polymyxins in vitro, disulfiram could augment the bactericidal effect against E. coli or A. baumannii. When combined with colistin in vivo, disulfiram also protected against murine E. coli infection. Disulfiram inhibited the motility of E. coli but did not change its length morphologically. Transcriptomic analysis revealed that disulfiram-treated E. coli presented an oxidative stress pattern and zinc-related transcriptomic changes. Moreover, the bacteriostatic effect of disulfiram on E. coli and S. aureus could be fully prevented by the ROS scavenger NAC. In addition, zinc ions increased ROS levels and further suppressed bacterial growth, whereas zinc chelators suppressed ROS and restored the growth of both E. coli and S. aureus. This study reveals that disulfiram inhibits bacterial growth by inducing zinc-dependent intracellular reactive oxygen species (ROS). This bacteriostatic effect can be reversed by ROS scavengers or zinc chelators, highlighting a previously uncharacterized antimicrobial mechanism for disulfiram.

ORGANISM(S): Escherichia coli

PROVIDER: GSE299097 | GEO | 2025/06/05

REPOSITORIES: GEO

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Project description:Purpose: Free nitrous acid (FNA) has recently been demonstrated as an antimicrobial agent to a range of microorganisms. However, its antimicrobial mechanism is largely unknown. For this study Pseudomonas aeruginosa PAO1 was selected to gain a systematic understanding of the antimicrobial mechanism of FNA. Methods: PAO1 was grown under anaerobic denitrifying conditions and when FNA was added (0.1 mg-N/L) growth temporarily stopped. From cultures with and without added FNA, RNA was extracted and the abundance of gene transcripts was detected by sequencing. Transcripts exhibiting â¥2.5 or â¤-2.5 fold abundance change in the presence of FNA were designated as differentially expressed. Results:In response to FNA, 167 genes showed increased transcription while 424 exhibited deceased transcript levels. Respiration was likely inhibited as denitrification activity was severely decreased. Genes coding for enzymes of the tricarboxylic acid cycle were down regulated, while highly increased transcripts were detected for pyruvate fermentation, indicating a possible survival response to FNA. Moreover, genes coding ribosomal proteins had significantly decreased transcript levels, implicating that protein biosynthesis was severely inhibited by FNA. Whereas, genes encoding proteins functioning to preserve ribosome units under stressful conditions, were up-regulated during FNA exposure. Conclusion: In this study, we performed genome-wide high throughput RNA sequencing (RNA-Seq) analysis on PAO1 in the absence and presence of a bacteriostatic-level of FNA (0.1 mg N/L). By combining the global activated/suppressed gene profiles and detected physiological responses, we detected the microbial response to FNA exposure and revealed potential antimicrobial mechanisms of FNA on this prevalent opportunistic pathogen and environmentally relevant denitrifier. mRNA profiles of P. aeruginosa PAO1 towards FNA stress were generated by next generation sequencing in triplicate via Illumina 2000.

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Disulfiram inhibits bacterial growth by inducing zinc-dependent reactive oxygen species

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