{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T07:59:19Z","timestamp":1792569559084,"version":"4.5.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T00:00:00Z","timestamp":1674172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"NIGMS","doi-asserted-by":"publisher","award":["5F30GM139246-02"],"award-info":[{"award-number":["5F30GM139246-02"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:p>Despite the availability of several vaccines against multiple disease-causing strains of <jats:italic>Streptococcus pneumoniae<\/jats: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. <jats:italic>N,N-dimethyldithiocarbamate<\/jats:italic> (DMDC) was found to be a potent copper-dependent antimicrobial against several pathogens, including <jats:italic>S. pneumoniae<\/jats:italic>. Here, DMDCs efficacy against <jats:italic>Streptococcal<\/jats:italic> pathogens <jats:italic>Streptococcus pyogenes<\/jats:italic>, <jats:italic>Streptococcus agalactiae<\/jats:italic>, and <jats:italic>Streptococcus anginosus<\/jats: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\u2019 effectiveness as copper chelators using DsRed2 and as copper-dependent antimicrobials against <jats:italic>S. pneumoniae<\/jats:italic> TIGR4 and tested in bactericidal and animal models. Two compounds, sodium <jats:italic>N<\/jats:italic>-benzyl-<jats:italic>N<\/jats:italic>-methyldithiocarbamate and sodium <jats:italic>N<\/jats:italic>-allyl-<jats:italic>N<\/jats:italic>-methyldithiocarbamate (herein \u201cCompound 3\u201d and \u201cCompound 4\u201d), were effective against TIGR4 and further, D39 and ATCC\u00ae 6303\u2122 _(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 <jats:italic>in vivo<\/jats:italic> murine pneumonia model, Compound 3, but not Compound 4, was effective in significantly decreasing the bacterial burden in the blood and lungs of <jats:italic>S. pneumoniae<\/jats: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.<\/jats:p>","DOI":"10.3389\/fmicb.2022.1099330","type":"journal-article","created":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T05:05:30Z","timestamp":1674191130000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Novel dithiocarbamate derivatives are effective copper-dependent antimicrobials against Streptococcal species"],"prefix":"10.3389","volume":"13","author":[{"given":"Sanjay V.","family":"Menghani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamil","family":"Sanchez-Rosario","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chansorena","family":"Pok","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renshuai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"O\u2019Brien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda J.","family":"Neubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klariza","family":"Ochoa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredythe","family":"Durckel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riley D.","family":"Hellinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Hackett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D. 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Oral Microbiol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/S0021-9258(18)91491-2","article-title":"A method for the estimation of reducing sugars","volume":"9","author":"Benedict","year":"1911","journal-title":"J. Biol. Chem."},{"key":"ref4","volume-title":"Antibiotic resistance threats in the United States, 2019","year":"2019"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"105474","DOI":"10.1016\/j.bioorg.2021.105474","article-title":"Dithiocarbamates combined with copper for revitalizing meropenem efficacy against NDM-1-producing Carbapenem-resistant Enterobacteriaceae","volume":"118","author":"Chen","year":"2022","journal-title":"Bioorg. Chem."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1039\/c9mt00294d","article-title":"Changes in mammalian copper homeostasis during microbial infection","volume":"12","author":"Culbertson","year":"2020","journal-title":"Metallomics"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"4835","DOI":"10.1128\/AAC.00692-15","article-title":"Disulfiram and copper ions kill mycobacterium tuberculosis in a synergistic manner","volume":"59","author":"Dalecki","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"e00077","DOI":"10.1128\/CMR.00077-17","article-title":"Antibiotic hybrids: the next generation of agents and adjuvants against gram-negative pathogens?","volume":"31","author":"Domalaon","year":"2018","journal-title":"Clin. Microbiol. 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Chem."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1038\/s41564-019-0357-1","article-title":"Drug repurposing for antimicrobial discovery","volume":"4","author":"Farha","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1046\/j.1365-2958.2002.02832.x","article-title":"A genome-wide strategy for the identification of essential genes in Staphylococcus aureus","volume":"43","author":"Forsyth","year":"2002","journal-title":"Mol. Microbiol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e1008952","DOI":"10.1371\/journal.ppat.1008952","article-title":"COP9 signalosome is an essential and druggable parasite target that regulates protein degradation","volume":"16","author":"Ghosh","year":"2020","journal-title":"PLoS Pathog."},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.ARBA-0008-2017","article-title":"Antimicrobial Resistance in Streptococcus spp","volume":"6","author":"Haenni","year":"2018","journal-title":"Microbiol. 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Immunol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.poly.2010.09.023","article-title":"Anagostic interactions, revisiting the crystal structure of nickel dithiocarbamate complex and its antibacterial and antifungal studies","volume":"30","author":"Husain","year":"2011","journal-title":"Polyhedron"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"2266","DOI":"10.1126\/science.1063566","article-title":"Identification of critical staphylococcal genes using conditional phenotypes generated by antisense RNA","volume":"293","author":"Ji","year":"2001","journal-title":"Science"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"9032","DOI":"10.1038\/s41598-020-65977-z","article-title":"Clinical characteristics of infections caused by Streptococcus anginosus group","volume":"10","author":"Jiang","year":"2020","journal-title":"Sci. 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Virol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"20709","DOI":"10.1039\/C5NR05838D","article-title":"Real-time scattered light dark-field microscopic imaging of the dynamic degradation process of sodium dimethyldithiocarbamate","volume":"7","author":"Lei","year":"2015","journal-title":"Nanoscale"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"585","DOI":"10.3290\/j.ohpd.a43165","article-title":"An analysis of resistance patterns of Oral streptococci obtained from orofacial infections against Beta-lactams, clindamycin and vancomycin over 2014-2018","volume":"17","author":"Leszczynski","year":"2019","journal-title":"Oral Health Prev. Dent."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.3390\/microorganisms8071055","article-title":"Multidrug-resistant Streptococcus agalactiae strains found in human and fish with high penicillin and cefotaxime non-susceptibilities","volume":"8","author":"Li","year":"2020","journal-title":"Microorganisms"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"e0059721","DOI":"10.1128\/iai.00597-21","article-title":"N,N-Dimethyldithiocarbamate elicits pneumococcal hypersensitivity to copper and macrophage-mediated clearance","volume":"90","author":"Menghani","year":"2022","journal-title":"Infect. Immun."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e0077821","DOI":"10.1128\/Spectrum.00778-21","article-title":"Demonstration of N,N-Dimethyldithiocarbamate as a copper-dependent antibiotic against multiple upper respiratory tract pathogens","volume":"9","author":"Menghani","year":"2021","journal-title":"Microbiol. Spectr."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1128\/mSphere.00411-20","article-title":"Rules of expansion: an updated consensus operator site for the CopR-CopY family of bacterial copper exporter system repressors","volume":"5","author":"O\u2019brien","year":"2020","journal-title":"mSphere"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"633","DOI":"10.3390\/antibiotics9090633","article-title":"Repurposing disulfiram (Tetraethylthiuram disulfide) as a potential drug candidate against Borrelia burgdorferi in vitro and in vivo","volume":"9","author":"Potula","year":"2020","journal-title":"Antibiotics"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1073\/pnas.97.2.652","article-title":"CopA: an Escherichia coli cu(I)-translocating P-type ATPase","volume":"97","author":"Rensing","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1186\/1471-2180-12-215","article-title":"Molecular epidemiology, antimicrobial susceptibilities and resistance mechanisms of streptococcus pyogenes isolates resistant to erythromycin and tetracycline in Spain (1994-2006)","volume":"12","author":"Rubio-Lopez","year":"2012","journal-title":"BMC Microbiol."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"104346","DOI":"10.1016\/j.bioorg.2020.104346","article-title":"An insight into medicinal attributes of dithiocarbamates: Bird's eye view","volume":"105","author":"Shinde","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"633194","DOI":"10.3389\/fcimb.2021.633194","article-title":"Drug repurposing of the alcohol abuse medication disulfiram as an anti-parasitic agent","volume":"11","author":"Shirley","year":"2021","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e00478-20","DOI":"10.1128\/JB.00478-20","article-title":"Targeting the Achilles' heel of bacteria: different mechanisms to break down the peptidoglycan Cell Wall during bacterial warfare","volume":"203","author":"Sibinelli-Sousa","year":"2021","journal-title":"J. Bacteriol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1042\/BJ20071620","article-title":"Structure and cu(I)-binding properties of the N-terminal soluble domains of Bacillus subtilis CopA","volume":"411","author":"Singleton","year":"2008","journal-title":"Biochem. J."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"27608","DOI":"10.1073\/pnas.1920015117","article-title":"Synthetic gene-regulatory networks in the opportunistic human pathogen Streptococcus pneumoniae","volume":"117","author":"Sorg","year":"2020","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1016\/j.bios.2005.04.023","article-title":"DsRed as a highly sensitive, selective, and reversible fluorescence-based biosensor for both cu(+) and cu(2+) ions","volume":"21","author":"Sumner","year":"2006","journal-title":"Biosens. Bioelectron."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"3745","DOI":"10.2147\/IDR.S227883","article-title":"The pathogenesis of Streptococcus anginosus in aerobic vaginitis","volume":"12","author":"Tao","year":"2019","journal-title":"Infect. Drug Resist."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/s41579-018-0147-4","article-title":"Methicillin-resistant Staphylococcus aureus: an overview of basic and clinical research","volume":"17","author":"Turner","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"3436","DOI":"10.1016\/j.bmcl.2018.09.028","article-title":"Dithiocarbamates: efficient metallo-\u03b2-lactamase inhibitors with good antibacterial activity when combined with meropenem","volume":"28","author":"Wang","year":"2018","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1111\/j.1742-4658.2011.08422.x","article-title":"Cu(I)- and proton-binding properties of the first N-terminal soluble domain of Bacillus subtilis CopA","volume":"279","author":"Zhou","year":"","journal-title":"FEBS J."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"5939","DOI":"10.1039\/c2dt30126a","article-title":"CopAb, the second N-terminal soluble domain of Bacillus subtilis CopA, dominates the cu(I)-binding properties of CopAab","volume":"41","author":"Zhou","year":"","journal-title":"Dalton Trans."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.vaccine.2021.12.008","article-title":"Invasive Streptococcus pneumoniae isolates from pediatric population in Argentina for the period 2006-2019. 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