N,N-Dimethyldithiocarbamate Elicits Pneumococcal Hypersensitivity to Copper and Macrophage-Mediated Clearance

Sanjay V. Menghani, Madeline P. Cutcliffe, Yamil Sanchez-Rosario, Chansorena Pok, Alison Watson, Miranda J. Neubert, Klariza Ochoa, Hsin Jung Joyce Wu, Michael D.L. Johnson

Research output: Contribution to journalArticlepeer-review

Abstract

Streptococcus pneumoniae is a Gram-positive, encapsulated bacterium that is a significant cause of disease burden in pediatric and elderly populations. The rise in unencapsulated disease-causing strains and antimicrobial resistance in S. pneumoniae has increased the need for developing new antimicrobial strategies. Recent work by our laboratory has identified N,N-dimethyldithiocarbamate (DMDC) as a copper-dependent antimicrobial against bacterial, fungal, and parasitic pathogens. As a bactericidal antibiotic against S. pneumoniae, DMDC’s ability to work as a copper-dependent antibiotic and its ability to work in vivo warranted further investigation. Here, our group studied the mechanisms of action of DMDC under various medium and excess-metal conditions and investigated DMDC’s interactions with the innate immune system in vitro and in vivo. Of note, we found that DMDC plus copper significantly increased the internal copper concentration, hydrogen peroxide stress, nitric oxide stress, and the in vitro macrophage killing efficiency and decreased capsule. Furthermore, we found that in vivo DMDC treatment increased the quantity of innate immune cells in the lung during infection. Taken together, this study provides mechanistic insights regarding DMDC’s activity as an antibiotic at the host-pathogen interface.

Original languageEnglish (US)
JournalInfection and Immunity
Volume90
Issue number4
DOIs
StatePublished - Apr 2022

Keywords

  • Antibiotic
  • Antimicrobial activity
  • Antimicrobial combinations
  • Copper
  • Copper-dependent toxicity
  • DMDC
  • Dimethyldithiocarbamate
  • Flow cytometry
  • Macrophages
  • Metal
  • Streptococcus pneumoniae

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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