3280e5337b2c931615ecdb04d6c064d9 antibiotics-11-01752-v2.pdf e5454bbb5223a0f44fea77ebba7199e31728ac81 antibiotics-11-01752-v2.pdf b2e9e2c8013f2d8c79d41fef4ab3a4def8cb275e4c6bace7ab5f142566bc9f94 antibiotics-11-01752-v2.pdf Title: Repurposing Disulfiram as an Antimicrobial Agent in Topical Infections Subject: Antimicrobial drugs applied topically offer several advantages. However, the widespread use of antibiotics has led to increasing antimicrobial resistance. One interesting approach in the drug discovery process is drug repurposing. Disulfiram, which was originally approved as an anti-alcoholism drug, offers an attractive alternative to treat topical multidrug resistance bacteria in skin human infections. This study aimed to evaluate the biopharmaceutical characteristics of the drug and the effects arising from its topical application in detail. Microdilution susceptibility testing showed antibacterial activity against Gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes. Dermal absorption revealed no permeation in pig skin. The quantification of the drug retained in pig skin demonstrated concentrations in the stratum corneum and epidermis, enough to treat skin infections. Moreover, in vitro cytotoxicity and micro-array analyses were performed to better understand the mechanism of action and revealed the importance of the drug as a metal ion chelator. Together, our findings suggest that disulfiram has the potential to be repurposed as an effective antibiotic to treat superficial human skin infections. Keywords: disulfiram; skin; Staphylococcus aureus; repurposing; DNA arrays; antibiotics;antimicrobial resistance; Streptococcus pyogenes Author: Maria Lajarin-Reinares, Eloy Pena-Rodríguez, Mariona Cañellas-Santos, Elisabet Rosell-Vives, Pilar Cortés, Montserrat Llagostera Casas, Maria Àngels Calvo and Francisco Fernandez-Campos Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Dec 7 09:13:59 2022 CET ModDate: Wed Dec 7 09:46:54 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1006145 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- MPSUUM+VnURWPalladioL Type 1 Custom yes yes no 10 0 UKJIMJ+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 AFKKWC+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 MIMPKJ+URWPalladioL-Ital Type 1 Custom 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Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Ex Vivo Skin Absorption Experiment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Quantification of Disulfiram in Skin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Children: Item: Title: Quantification of D in SC Using the Tape-Stripping Technique Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Disulfiram Concentration Retained in the Dermatomized Skin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: In Vitro Cytotoxicity Evaluation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Functional Analysis of Expressed Genes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Children: Item: Title: Materials Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Antibiotic Susceptibility Testing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Production of Disulfiram Emulsion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Ex Vivo Skin Absorption Experiment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Quantification of Disulfiram in Skin after Permeation Experiments Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Children: Item: Title: Determination of Pig Skin Density Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Tape-Stripping Study Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Determination of the Concentration Retained in the Dermatomized Skin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: In Vitro Cytotoxicity Evaluation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Microarrays and Data Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Info: Title: Repurposing Disulfiram as an Antimicrobial Agent in Topical Infections Author: Maria Lajarin-Reinares, Eloy Pena-Rodríguez, Mariona Cañellas-Santos, Elisabet Rosell-Vives, Pilar Cortés, Montserrat Llagostera Casas, Maria Àngels Calvo and Francisco Fernandez-Campos Subject: Antimicrobial drugs applied topically offer several advantages. However, the widespread use of antibiotics has led to increasing antimicrobial resistance. One interesting approach in the drug discovery process is drug repurposing. Disulfiram, which was originally approved as an anti-alcoholism drug, offers an attractive alternative to treat topical multidrug resistance bacteria in skin human infections. This study aimed to evaluate the biopharmaceutical characteristics of the drug and the effects arising from its topical application in detail. Microdilution susceptibility testing showed antibacterial activity against Gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes. Dermal absorption revealed no permeation in pig skin. The quantification of the drug retained in pig skin demonstrated concentrations in the stratum corneum and epidermis, enough to treat skin infections. Moreover, in vitro cytotoxicity and micro-array analyses were performed to better understand the mechanism of action and revealed the importance of the drug as a metal ion chelator. Together, our findings suggest that disulfiram has the potential to be repurposed as an effective antibiotic to treat superficial human skin infections. 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