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

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.

Compounds derived from N,N-dimethyldithiocarbamate are effective copper-dependent antimicrobials against Streptococcus pneumoniae

“…We observed a significant decrease in bacterial titers in the blood and lungs 48 hours post-infection in 8-week-old BALB/c mice given 25 µL of 10 mM Compound 3 (approximately 1.6 mg/kg), but no significant decrease was noted for mice given the same dosage of Compound 4 (Figure 5A-D). Further, as previously observed with DMDC and copper (21), the combination treatment of Compound 3 plus copper also made the pneumococcus more susceptible to activated macrophage mediated killing via a macrophage killing assay as compared to no treatment, copper, or Compound 3 alone (Figure 6). These data show that Compound 3 is a promising antibiotic against S. pneumoniae TIGR4 with efficacy in vivo .…”

“…Compound 3 and Compound 4 showed in vitro inhibition in growth curves against TIGR4 while Compound 1, Compound 2, and Compound 5 had no effect (Figure 1 and Table 1). Further, Compounds 3 and 4 had seemingly increased killing capacity after 30 minutes compared to DMDC, which didn't start showing killing until the 60 minute time point, thus indicating potential advancement in modifying dithiocarbamates as a copper dependent antimicrobial (21). After identifying that these DMDC derivatives could force copper into the bacteria and chelate copper, we observed a reduced bacterial burden during a murine respiratory infection using Compound 3 (Figure 2, 3, 4, 5, 7, 8).…”

“…Mechanistically, DMDC significantly increases the intrabacterial concentration of copper, putting stress on the bacteria to export copper before mismetallation inactivates or reduces the efficiency of key bacterial enzymes, eventually leading to bacterial death (20, 21). Further, when the excess oxidized copper enters the bacteria, it diminishes the reductive capacity of the bacteria, which must reduce copper ions in order to export them (21-26).…”

“…Mechanistically, DMDC significantly increases the intrabacterial concentration of copper, putting stress on the bacteria to export copper before mismetallation inactivates or reduces the efficiency of key bacterial enzymes, eventually leading to bacterial death (20, 21). Further, when the excess oxidized copper enters the bacteria, it diminishes the reductive capacity of the bacteria, which must reduce copper ions in order to export them (21-26). As a result, the pneumococcus cannibalized its capsule, making macrophage mediating killing more efficient, and presumably to extract electrons from the sugar building blocks to maintain the intrabacterial reducing environment (21, 27).…”

“…Mechanistically, DMDC significantly increases the intrabacterial concentration of copper, putting stress on the bacteria to export copper before mismetallation inactivates or reduces the efficiency of key bacterial enzymes, eventually leading to bacterial death (20,21).…”