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

Abstract

N,N-dimethyldithiocarbamate (DMDC) is a potent copper-dependent antimicrobial against several pathogens, including Streptococcus pneumoniae. Despite the availability of several vaccines against multiple disease-causing strains of S. pneumoniae, the rise of antimicrobial resistance and pneumococcal disease caused by strains not covered by the vaccine creates a need for developing novel antimicrobial strategies. We derived novel compounds from DMDC and tested their effectiveness as copper-dependent antimicrobials against S. pneumoniae through in vitro growth and killing curves. Compounds that caused a growth defect and were bactericidal in vitro were tested against other strains of S. pneumoniae and in complex with different transition metals. We found two compounds, sodium N-benzyl-N-methyldithiocarbamate and sodium N-allyl-N-methyldithiocarbamate (herein "Compound 3" and "Compound 4"), were effective against TIGR4, D39, and ATCC(R) 6303 (a type 3 capsular strain) and further increased the internal concentrations of copper to the same previously reported levels as with DMDC and copper treatment. We found that both Compound 3 and Compound 4 were bacteriostatic in combination with zinc. We tested Compound 3 and Compound 4 in vivo against a murine pneumonia model, finding that Compound 3, and not Compound 4, was effective in significantly decreasing the bacterial burden in the blood and lungs of S. pneumoniae-infected mice. We found that the combination of Compound 3 and copper made the pneumococcus more susceptible to activated macrophage mediated killing via an in vitro macrophage killing assay. Collectively, we demonstrate that derivatizing DMDC holds promise as potent bactericidal antibiotics against S. pneumoniae.