title: Identification of N-Arylated NH125 Analogues as Rapid Eradicating Agents against MRSA Persister Cells and Potent Biofilm Killers of Gram-Positive Pathogens.
abstract: Bacterial biofilms housing dormant persister cells are innately tolerant to antibiotics and disinfectants, yet several membrane-active agents are known to eradicate tolerant bacterial cells. NH125, a membrane-active persister killer and starting point for development, led to the identification of two N-arylated analogues (1 and 2) that displayed improved biofilm eradication potencies compared to the parent compound and rapid persister-cell-killing activities in stationary cultures of methicillin-resistant Staphylococcus aureus (MRSA). We found 1 and 2 to be superior to other membrane-active agents in biofilm eradication assays, with 1 demonstrating minimum biofilm eradication concentrations (MBEC) of 23.5, 11.7, and 2.35 μm against MRSA, methicillin-resistant Staphylococcus epidermidis (MRSE), and vancomycin-resistant Enterococcus faecium (VRE) biofilms, respectively. We tested our panel of membrane-active agents against MRSA stationary cultures and found 1 to rapidly eradicate MRSA stationary cells by 4 log units (99.99 %) in 30 min. The potent biofilm eradication and rapid persister-cell-killing activities exhibited by N-arylated NH125 analogues could have significant impact in addressing biofilm-associated problems.
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Abouelhassan
authors.affiliation: Department of Chemistry, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Basak
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
authors.forename: Hussain
authors.initials: H
authors.lastname: Yousaf
authors.affiliation: Department of Medicinal Chemistry, Center for Natural Products Drug Discovery and Development (CNPD3), College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.|Department of Chemistry, University of Florida, 1600 SW Archer Road, Gainesville, FL, 32610, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Huigens
mesh_terms: D000081:Acetamides / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects*; D004912:Erythrocytes / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D007093:Imidazoles; C114284:N-(4-bromo-2-(2-pyridylcarbonyl)phenyl)-2-aminoacetamide; C414024:NH 125; D011725:Pyridines
keywords: MRSA; antibacterial agents; biofilms; drug-resistant bacteria; persister cells