title: Halogenated Phenazines that Potently Eradicate Biofilms, MRSA Persister Cells in Non-Biofilm Cultures, and Mycobacterium tuberculosis.
abstract: Conventional antibiotics are ineffective against non-replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1, that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC = 0.2-12.5 μM), as well as the effective killing of MRSA persister cells in non-biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non-biofilm persisters alongside 14. HP 13 displayed potent antibacterial activity against slow-growing M. tuberculosis (MIC = 3.13 μM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non-toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Dr., Gainesville, FL 32610 (USA).
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Garrison
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Dr., Gainesville, FL 32610 (USA).
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Abouelhassan
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Dr., Gainesville, FL 32610 (USA).
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kallifidas
authors.affiliation: Department of Molecular Genetics & Microbiology, University of Florida (USA).
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Epidemiology, University of Florida, P.O. Box 100009, Gainesville, FL 32610 (USA).
authors.forename: Maria
authors.initials: M
authors.lastname: Ukhanova
authors.affiliation: Department of Epidemiology, University of Florida, P.O. Box 100009, Gainesville, FL 32610 (USA).
authors.forename: Volker
authors.initials: V
authors.lastname: Mai
authors.affiliation: Department of Molecular Genetics & Microbiology, University of Florida (USA).
authors.forename: Shouguang
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Dr., Gainesville, FL 32610 (USA).
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, 1345 Center Dr., Gainesville, FL 32610 (USA). rhuigens@cop.ufl.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Huigens
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000166:cytology* / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D010619:Phenazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D010619:Phenazines
keywords: bacterial biofilms; biofilm eradication; halogenated phenazines; marine antibiotics; medicinal chemistry