AUTHOR=Menghani Sanjay V. , Sanchez-Rosario Yamil , Pok Chansorena , Liu Renshuai , Gao Feng , O’Brien Henrik , Neubert Miranda J. , Ochoa Klariza , Durckel Meredythe , Hellinger Riley D. , Hackett Nadia , Wang Wei , Johnson Michael D. L. 

TITLE=Novel dithiocarbamate derivatives are effective copper-dependent antimicrobials against Streptococcal species

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.1099330

DOI=10.3389/fmicb.2022.1099330

ISSN=1664-302X

ABSTRACT=<p>Despite the availability of several vaccines against multiple disease-causing strains of <italic>Streptococcus pneumoniae</italic>, the rise of antimicrobial resistance and pneumococcal disease caused by strains not covered by the vaccine creates a need for developing novel antimicrobial strategies. <italic>N,N-dimethyldithiocarbamate</italic> (DMDC) was found to be a potent copper-dependent antimicrobial against several pathogens, including <italic>S. pneumoniae</italic>. Here, DMDCs efficacy against <italic>Streptococcal</italic> pathogens <italic>Streptococcus pyogenes</italic>, <italic>Streptococcus agalactiae</italic>, and <italic>Streptococcus anginosus</italic> was tested using bactericidal and inductively coupled plasma - optical emission spectrometry. After confirming DMDC as broad-spectrum streptococcal antimicrobial, DMDC was derivatized into five compounds. The derivatives’ effectiveness as copper chelators using DsRed2 and as copper-dependent antimicrobials against <italic>S. pneumoniae</italic> TIGR4 and tested in bactericidal and animal models. Two compounds, sodium <italic>N</italic>-benzyl-<italic>N</italic>-methyldithiocarbamate and sodium <italic>N</italic>-allyl-<italic>N</italic>-methyldithiocarbamate (herein “Compound 3” and “Compound 4”), were effective against TIGR4 and further, D39 and ATCC® 6303™ _(a type 3 capsular strain). Both Compound 3 and 4 increased the pneumococcal internal concentrations of copper to the same previously reported levels as with DMDC and copper treatment. However, in an <italic>in vivo</italic> murine pneumonia model, Compound 3, but not Compound 4, was effective in significantly decreasing the bacterial burden in the blood and lungs of <italic>S. pneumoniae</italic>-infected mice. These derivatives also had detrimental effects on the other streptococcal species. Collectively, derivatizing DMDC holds promise as potent bactericidal antibiotics against relevant streptococcal pathogens.</p>