title: Membrane active phenylalanine conjugated lipophilic norspermidine derivatives with selective antibacterial activity.
abstract: Natural and synthetic membrane active antibacterial agents offer hope as potential solutions to the problem of bacterial resistance as the membrane-active nature imparts low propensity for the development of resistance. In this report norspermidine based antibacterial molecules were developed that displayed excellent antibacterial activity against various wild-type bacteria (Gram-positive and Gram-negative) and drug-resistant bacteria (methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and β-lactam-resistant Klebsiella pneumoniae). In a novel structure-activity relationship study it has been shown how incorporation of an aromatic amino acid drastically improves selective antibacterial activity. Additionally, the effect of stereochemistry on activity, toxicity, and plasma stability has also been studied. These rapidly bactericidal, membrane active antibacterial compounds do not trigger development of resistance in bacteria and hence bear immense potential as therapeutic agents to tackle multidrug resistant bacterial infections.
authors.affiliation: Chemical Biology and Medicinal Chemistry Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research , Jakkur, Bengaluru 560064, Karnataka, India.
authors.forename: Mohini M
authors.initials: MM
authors.lastname: Konai
authors.forename: Chandradhish
authors.initials: C
authors.lastname: Ghosh
authors.forename: Venkateswarlu
authors.initials: V
authors.lastname: Yarlagadda
authors.forename: Sandip
authors.initials: S
authors.lastname: Samaddar
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001424:Bacterial Infections / Q000188:drug therapy; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D016984:Enterococcus faecium; D006801:Humans; D007700:Kinetics; D007711:Klebsiella pneumoniae; D055624:Methicillin-Resistant Staphylococcus aureus; D008823:Micelles; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D010649:Phenylalanine / Q000138:chemical synthesis / Q000737:chemistry*; D010949:Plasma / Q000187:drug effects / Q000382:microbiology; D044967:Serum / Q000187:drug effects / Q000382:microbiology; D013095:Spermidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013778:Tetrazolium Salts / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D014640:Vancomycin / Q000737:chemistry; D047090:beta-Lactams / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D008823:Micelles; D013778:Tetrazolium Salts; D013844:Thiazoles; D047090:beta-Lactams; D010649:Phenylalanine; C006760:norspermidine; D014640:Vancomycin; C022616:thiazolyl blue; D013095:Spermidine