TY - JOUR
T1 - N,N-Dimethyldithiocarbamate Elicits Pneumococcal Hypersensitivity to Copper and Macrophage-Mediated Clearance
AU - Menghani, Sanjay V.
AU - Cutcliffe, Madeline P.
AU - Sanchez-Rosario, Yamil
AU - Pok, Chansorena
AU - Watson, Alison
AU - Neubert, Miranda J.
AU - Ochoa, Klariza
AU - Wu, Hsin Jung Joyce
AU - Johnson, Michael D.L.
N1 - Publisher Copyright:
Copyright © 2022 Menghani et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
KW - Antibiotic
KW - Antimicrobial activity
KW - Antimicrobial combinations
KW - Copper
KW - Copper-dependent toxicity
KW - DMDC
KW - Dimethyldithiocarbamate
KW - Flow cytometry
KW - Macrophages
KW - Metal
KW - Streptococcus pneumoniae
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U2 - 10.1128/iai.00597-21
DO - 10.1128/iai.00597-21
M3 - Article
C2 - 35311543
AN - SCOPUS:85128649713
SN - 0019-9567
VL - 90
JO - Infection and Immunity
JF - Infection and Immunity
IS - 4
ER -