title: Antibacterial Diamines Targeting Bacterial Membranes.
abstract: Antibiotic resistance is a growing threat to human health exacerbated by a lack of new antibiotics. We now describe a series of substituted diamines that produce rapid bactericidal activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and stationary-phase bacteria. These compounds reduce biofilm formation and promote biofilm dispersal in Pseudomonas aeruginosa. The most potent analogue, 3 (1,13-bis{[(2,2-diphenyl)-1-ethyl]thioureido}-4,10-diazatridecane), primarily acts by depolarization of the cytoplasmic membrane and permeabilization of the bacterial outer membrane. Transmission electron microscopy confirmed that 3 disrupts membrane integrity rapidly. Compound 3 is also synergistic with kanamycin, demonstrated by the checkerboard method and by time-kill kinetic experiments. In human cell toxicity assays, 3 showed limited adverse effects against the HEK293T human kidney embryonic cells and A549 human adenocarcinoma cells. In addition, 3 produced no adverse effects on Caenorhabditis elegans development, survival, and reproduction. Collectively, diamines related to 3 represent a new class of broad-spectrum antibacterials against drug-resistant pathogens.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina , Charleston, South Carolina 29425, United States.|Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing, PR China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina , Charleston, South Carolina 29425, United States.
authors.forename: Boobalan
authors.initials: B
authors.lastname: Pachaiyappan
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina , Charleston, South Carolina 29425, United States.
authors.forename: Jordon D
authors.initials: JD
authors.lastname: Gruber
authors.affiliation: Department of Microbiology & Immunology, Medical University of South Carolina , Charleston, South Carolina 29425, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schmidt
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina , Charleston, South Carolina 29425, United States.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina , Charleston, South Carolina 29425, United States.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Woster
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000254:growth & development; D002462:Cell Membrane / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003959:Diamines / Q000737:chemistry* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004347:Drug Interactions; D004926:Escherichia coli / Q000187:drug effects; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D003959:Diamines