title: Minor groove DNA binders as antimicrobial agents. 1. Pyrrole tetraamides are potent antibacterials against vancomycin resistant Enterococci [corrected] and methicillin resistant Staphylococcus aureus.
abstract: A new series of short pyrrole tetraamides are described whose submicromolar DNA binding affinity is an essential component for their strong antibacterial activity. This class of compounds is related to the linked bis-netropsins and bis-distamycins, but here, only one amino-pyrrole-carboxamide unit and an amidine tail is connected to either side of a central dicarboxylic acid linker. The highest degree of DNA binding, measured by compound-induced changes in UV melting temperatures of an AT-rich DNA oligomer, was observed for flat, aromatic linkers with no inherent bent, i.e., terephthalic acid or 1,4-pyridine-dicarboxylic acid. However, the antibacterial activity is critically linked to the size of the N-alkyl substiutent of the pyrrole unit. None of the tetraamides with the commonly used methyl-pyrrole showed antibacterial activity. Isoamyl- or cyclopropylmethylene-substituted dipyrrole derivatives have the minimum inhibitory concentrations in the submicromolar range. In vitro toxicity against human T-cells was studied for all compounds. The degree to which compounds inhibited cell growth was neither directly correlated to DNA binding affinity nor directly correlated to antibacterial activity but seemed to depend strongly on the nature of the N-alkyl pyrrole substituents.
authors.affiliation: Genelabs Technologies, 505 Penobscot Drive, Redwood City, California 94063, USA. ndyatkina@genelabs.com
authors.forename: Natalia B
authors.initials: NB
authors.lastname: Dyatkina
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Roberts
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Keicher
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Dai
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Nadherny
authors.forename: Wentao
authors.initials: W
authors.lastname: Zhang
authors.forename: Uli
authors.initials: U
authors.lastname: Schmitz
authors.forename: Ana
authors.initials: A
authors.lastname: Kongpachith
authors.forename: Kevin
authors.initials: K
authors.lastname: Fung
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Novikov
authors.forename: Lillian
authors.initials: L
authors.lastname: Lou
authors.forename: Mark
authors.initials: M
authors.lastname: Velligan
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Khorlin
authors.forename: Ming S
authors.initials: MS
authors.lastname: Chen
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry*; D016983:Enterococcus / Q000187:drug effects*; D006801:Humans; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects; D014407:Tumor Cells, Cultured; D020713:Vancomycin Resistance
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D011758:Pyrroles; D004247:DNA