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
Department of Immunobiology, University of Arizona College of Medicine - Tucson, Tucson, AZ, United States.
Medical Scientist Training MD-PhD Program (MSTP), University of Arizona College of Medicine - Tucson, Tucson, AZ, United States.
Front Microbiol. 2023 Jan 20;13:1099330. doi: 10.3389/fmicb.2022.1099330. eCollection 2022.
Despite the availability of several vaccines against multiple disease-causing strains of , the rise of antimicrobial resistance and pneumococcal disease caused by strains not covered by the vaccine creates a need for developing novel antimicrobial strategies. (DMDC) was found to be a potent copper-dependent antimicrobial against several pathogens, including . Here, DMDCs efficacy against pathogens , , and 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 TIGR4 and tested in bactericidal and animal models. Two compounds, sodium -benzyl--methyldithiocarbamate and sodium -allyl--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 murine pneumonia model, Compound 3, but not Compound 4, was effective in significantly decreasing the bacterial burden in the blood and lungs of -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.
尽管有几种针对多种致病菌株的疫苗，但抗菌药物耐药性的上升以及疫苗未覆盖菌株引起的肺炎球菌疾病，使得开发新型抗菌策略成为必要。已发现二甲基二硫代氨基甲酸盐（DMDC）是一种对包括……在内的多种病原体有效的铜依赖性抗菌剂。在此，使用杀菌法和电感耦合等离子体发射光谱法测试了DMDC对肺炎链球菌病原体、、和的疗效。在确认DMDC为广谱链球菌抗菌剂后，将DMDC衍生为五种化合物。使用DsRed2测试了这些衍生物作为铜螯合剂的有效性，以及作为对肺炎链球菌TIGR4的铜依赖性抗菌剂，并在杀菌和动物模型中进行了测试。两种化合物，苄基甲基二硫代氨基甲酸钠和烯丙基甲基二硫代氨基甲酸钠（以下简称“化合物3”和“化合物4”）对TIGR4有效，此外，对D39和ATCC® 6303™（一种3型荚膜菌株）也有效。化合物3和4都将肺炎球菌内部的铜浓度提高到了与DMDC和铜处理相同的先前报道水平。然而，在小鼠肺炎模型中，化合物3（而非化合物4）能有效显著降低感染小鼠血液和肺部的细菌载量。这些衍生物对其他链球菌物种也有有害影响。总体而言，将DMDC衍生化有望成为针对相关链球菌病原体的强效杀菌抗生素。
