Warfarin analogs target disulfide bond-forming enzymes and suggest a residue important for quinone and coumarin binding.

Disulfide bond formation has a central role in protein folding of both eukaryotes and prokaryotes. In bacteria, disulfide bonds are catalyzed by DsbA and DsbB/VKOR enzymes. First, DsbA, a periplasmic disulfide oxidoreductase, introduces disulfide bonds into substrate proteins. Then, the membrane enzyme, either DsbB or VKOR, regenerate DsbA's activity by the formation of de novo disulfide bonds which reduce quinone. We have previously performed a high-throughput chemical screen and identified a family of warfarin analogs that target either bacterial DsbB or VKOR. In this work, we expressed functional human VKORc1 in Escherichia coli and performed a structure-activity-relationship analysis to study drug selectivity between bacterial and mammalian enzymes. We found that human VKORc1 can function in E. coli by removing two positive residues, allowing the search for novel anticoagulants using bacteria. We also found one warfarin analog capable of inhibiting both bacterial DsbB and VKOR and a second one antagonized only the mammalian enzymes when expressed in E. coli. The difference in the warfarin structure suggests that substituents at positions three and six in the coumarin ring can provide selectivity between the bacterial and mammalian enzymes. Finally, we identified the two amino acid residues responsible for drug binding. One of these is also essential for de novo disulfide bond formation in both DsbB and VKOR enzymes. Our studies highlight a conserved role of this residue in de novo disulfide-generating enzymes and enable the design of novel anticoagulants or antibacterials using coumarin as a scaffold.

Codeine dysregulates ribosome biogenesis in Escherichia coli with DNA double-strand breaks to chart path to new classes of antibiotics.

Aim: A bacterial genetics-guided approach was utilized for the discovery of new compounds affecting bacterial genome stability. Materials & methods: Fungal extracts and fractions were tested for genome instability-mediated antibacterial activity. Interaction assays and RT-qPCR were used to identify compounds that boost the activity of sub-minimum inhibitory concentration streptomycin and obtain insights on the molecular mechanisms of the primary hit compound, respectively. Results: Several extracts and fractions caused bacterial genome instability. Codeine, in synergy with streptomycin, regulates double-strand break (DSB) repair and causes bacterial ribosome dysfunction in the absence of DSBs, and dysregulation of ribosome biogenesis in a DSB-dependent manner. Conclusion: This study demonstrates a potential viable strategy that we are exploring for the discovery of new chemical entities with activities against Escherichia coli and other bacterial pathogens.

Prevalence of oral conditions and associated factors among schoolchildren in Accra, Ghana: a cross-sectional study.

OBJECTIVE: The impact of oral diseases on children cannot be overemphasized because their effects may go beyond the individual to the household and the community at large. This study aimed to determine the prevalence of common oral conditions in children between the ages of 9 and 16 years in Accra. METHODS: A cross-sectional study was carried out among participants from 16 selected junior high schools in Accra. Their caries experience was assessed using the decayed, missing, and filled teeth (DMFT) index. Other variables recorded were age, sex, previous history of a dental visit, and the presence of other common oral conditions (ie, periodontal disease, traumatised teeth, oral mucosal lesions, neoplasia, cysts, and malocclusion). Summaries and descriptive statistics were generated and reported. The DMFT was compared between subgroups, and the χ2 test was used to compare outcomes of categorical variables. RESULTS: A total of 1118 students participated in the study. This consisted of 37.8% males and 62.2% females. The mean age was 12.8 (standard deviation = 1.7) years. Common oral conditions were found in 49.7% of the participants and the prevalence of caries, periodontal disease, and malocclusion were found to be 13.3%, 30.4%, and 11.3%, respectively. The population's mean DMFT was found to be 0.27 (standard deviation = 0.76). CONCLUSIONS: The prevalence of caries and periodontal disease calls for additionaleffort to reduce the burden of common oral conditions in Ghanaian children.

Global Oral Health Policies and Guidelines: Using Silver Diamine Fluoride for Caries Control.

Silver diamine fluoride (SDF) was developed in Japan in the 1960s. It is a clear solution containing silver and fluoride ions. Because of its anti-bacterial and remineralizing effect, silver diamine fluoride has been used in managing dental caries for decades worldwide. This paper aims to summarize and discuss the global policies, guidelines, and relevant information on utilizing SDF for caries management. SDF can be used for treating dental caries in most countries. However, it is not permitted to be used in mainland China. Several manufacturers, mainly in Australia, Brazil, India, Japan, and the United States, produce SDF at different concentrations that are commercially available around the world. The prices differ between contents and brands. Different government organizations and dental associations have developed guidelines for clinical use of SDF. Dental professionals can refer to the specific guidelines in their own countries or territories. Training for using SDF is part of undergraduate and/or postgraduate curriculums in almost all countries. However, real utilization of SDF of dentists, especially in the private sector, remains unclear in most places because little research has been conducted. There are at least two ongoing regional-wide large-scale oral health programs, using SDF as one of the components to manage dental caries in young children (one in Hong Kong and one in Mongolia). Because SDF treatment does not require caries removal, and it is simple, non-invasive, and inexpensive, SDF is a valuable strategy for caries management in young children, elderly people, and patients with special needs. In addition, to reduce the risk of bacteria or virus transmission in dental settings, using SDF as a non-aerosol producing procedure should be emphasized under the COVID-19 outbreak.