title: Structure-Activity Relationships of a Diverse Class of Halogenated Phenazines That Targets Persistent, Antibiotic-Tolerant Bacterial Biofilms and Mycobacterium tuberculosis.
abstract: Persistent bacteria, including persister cells within surface-attached biofilms and slow-growing pathogens lead to chronic infections that are tolerant to antibiotics. Here, we describe the structure-activity relationships of a series of halogenated phenazines (HP) inspired by 2-bromo-1-hydroxyphenazine 1. Using multiple synthetic pathways, we probed diverse substitutions of the HP scaffold in the 2-, 4-, 7-, and 8-positions, providing critical information regarding their antibacterial and bacterial eradication profiles. Halogenated phenazine 14 proved to be the most potent biofilm-eradicating agent (≥99.9% persister cell killing) against MRSA (MBEC < 10 μM), MRSE (MBEC = 2.35 μM), and VRE (MBEC = 0.20 μM) biofilms while 11 and 12 demonstrated excellent antibacterial activity against M. tuberculosis (MIC = 3.13 μM). Unlike antimicrobial peptide mimics that eradicate biofilms through the general lysing of membranes, HPs do not lyse red blood cells. HPs are promising agents that effectively target persistent bacteria while demonstrating negligible toxicity against mammalian cells.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Garrison
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Abouelhassan
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Verrill M
authors.initials: VM
authors.lastname: Norwood
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kallifidas
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Fang
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Minh Thu
authors.initials: MT
authors.lastname: Nguyen
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rolfe
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Gena M
authors.initials: GM
authors.lastname: Burch
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Shouguang
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, ‡Department of Molecular Genetics & Microbiology, College of Medicine, and ⊥Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida , Gainesville, Florida 32610.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Huigens
mesh_terms: D018441:Biofilms / Q000187:drug effects*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006219:Halogens / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010619:Phenazines / Q000737:chemistry* / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship
chemical_list: D006219:Halogens; D010619:Phenazines