title: Coumarin-based inhibitors of Bacillus anthracis and Staphylococcus aureus replicative DNA helicase: chemical optimization, biological evaluation, and antibacterial activities.
abstract: The increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. Previously, we described coumarin-based inhibitors of an underexploited bacterial target, namely the replicative helicase. Here we report the synthesis and evaluation of optimized coumarin-based inhibitors with 9-18-fold increased potency against  Staphylococcus aureus  (Sa) and  Bacillus anthracis  (Ba) helicases. Compounds 20 and 22 provided the best potency, with IC(50) values of 3 and 1 μM, respectively, against the DNA duplex strand-unwinding activities of both  B. anthracis  and  S. aureus  helicases without affecting the single strand DNA-stimulated ATPase activity. Selectivity index (SI = CC(50)/MIC) values against  S. aureus  and  B. anthracis  for compound 20 were 33 and 66 and for compound 22 were 20 and 40, respectively. In addition, compounds 20 and 22 demonstrated potent antibacterial activity against multiple ciprofloxacin-resistant MRSA strains, with MIC values ranging between 0.5 and 4.2 μg/mL.
authors.affiliation: Microbiotix Inc., One Innovation Drive, Worcester, Massachusetts 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: Ming
authors.initials: M
authors.lastname: Di
authors.forename: Daniel
authors.initials: D
authors.lastname: Aiello
authors.forename: Marjorie H
authors.initials: MH
authors.lastname: Barnes
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Butler
authors.forename: Tommy F
authors.initials: TF
authors.lastname: Tashjian
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 / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001408:Bacillus anthracis / Q000187:drug effects / Q000201:enzymology*; D002939:Ciprofloxacin / Q000494:pharmacology; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004269:DNA, Bacterial / Q000235:genetics / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000235:genetics / Q000378:metabolism; D053488:DnaB Helicases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D057075:Enzyme Assays; D031541:Fluorescence Resonance Energy Transfer; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: C578800:3-(7-((4'-chlorobiphenyl-4-yl)methoxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)propanoic Acid; C578798:3-(7-(biphenyl-4-ylmethoxy)-4,8-dimethyl-2-oxo-2H-chromen-3-yl)propanoic Acid; D000900:Anti-Bacterial Agents; D003374:Coumarins; D004269:DNA, Bacterial; D004277:DNA, Single-Stranded; D002939:Ciprofloxacin; D053488:DnaB Helicases