title: Discovery, characterization and comparison of inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicases.
abstract: Antibacterial compounds with new mechanisms of action are needed for effective therapy against drug-resistant pathogens in the clinic and in biodefense. Screens for inhibitors of the essential replicative helicases of Bacillus anthracis and Staphylococcus aureus yielded 18 confirmed hits (IC(50)25 microM). Several (5 of 18) of the inhibitors were also shown to inhibit DNA replication in permeabilized polA-deficient B. anthracis cells. One of the most potent inhibitors also displayed antibacterial activity (MIC approximately 5 microg/ml against a range of Gram-positive species including bacilli and staphylococci) together with good selectivity for bacterial versus mammalian cells (CC(50)/MIC>16) suitable for further optimization. This compound shares the bicyclic ring of the clinically proven aminocoumarin scaffold, but is not a gyrase inhibitor. It exhibits a mixed mode of helicase inhibition including a component of competitive inhibition with the DNA substrate (K(i)=8 microM) and is rapidly bactericidal at 4 x MIC.
authors.affiliation: Microbiotix, Inc, Worcester, MA 01605, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aiello
authors.forename: Marjorie H
authors.initials: MH
authors.lastname: Barnes
authors.forename: Esther E
authors.initials: EE
authors.lastname: Biswas
authors.forename: Subhasis B
authors.initials: SB
authors.lastname: Biswas
authors.forename: Shen
authors.initials: S
authors.lastname: Gu
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
authors.forename: Donald T
authors.initials: DT
authors.lastname: Moir
mesh_terms: D049933:Aminocoumarins / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000187:drug effects* / Q000502:physiology; D001419:Bacteria / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D003001:Cloning, Molecular; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004269:DNA, Bacterial / Q000235:genetics; D050296:Microbial Viability / Q000187:drug effects; D008969:Molecular Sequence Data; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D049933:Aminocoumarins; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; D054852:Small Molecule Libraries; D004265:DNA Helicases