title: Optimization of a novel potent and selective bacterial DNA helicase inhibitor scaffold from a high throughput screening hit.
abstract: Benzobisthiazole derivatives were identified as novel helicase inhibitors through high throughput screening against purified Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) replicative helicases. Chemical optimization has produced compound 59 with nanomolar potency against the DNA duplex strand unwinding activities of both B. anthracis and S. aureus helicases. Selectivity index (SI=CC50/IC50) values for 59 were greater than 500. Kinetic studies demonstrated that the benzobisthiazole-based bacterial helicase inhibitors act competitively with the DNA substrate. Therefore, benzobisthiazole helicase inhibitors represent a promising new scaffold for evaluation as antibacterial agents.
authors.affiliation: Microbiotix Inc., One Innovation Drive, Worcester, MA 01605, USA. bli@microbiotix.com
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Ramdas
authors.initials: R
authors.lastname: Pai
authors.forename: Daniel
authors.initials: D
authors.lastname: Aiello
authors.forename: Ming
authors.initials: M
authors.lastname: Di
authors.forename: Marjorie H
authors.initials: MH
authors.lastname: Barnes
authors.forename: Norton P
authors.initials: NP
authors.lastname: Peet
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
authors.forename: Donald T
authors.initials: DT
authors.lastname: Moir
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001408:Bacillus anthracis / Q000201:enzymology; D001426:Bacterial Proteins / Q000235:genetics*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D057166:High-Throughput Screening Assays / Q000379:methods*; D008826:Microbial Sensitivity Tests / Q000379:methods; D013211:Staphylococcus aureus / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D052160:Benzothiazoles; D004269:DNA, Bacterial; D004791:Enzyme Inhibitors; D004265:DNA Helicases