title: Novel broad-spectrum bis-(imidazolinylindole) derivatives with potent antibacterial activities against antibiotic-resistant strains.
abstract: Given the limited number of structural classes of clinically available antimicrobial drugs, the discovery of antibacterials with novel chemical scaffolds is an important strategy in the development of effective therapeutics for both naturally occurring and engineered resistant strains of pathogenic bacteria. In this study, several diarylamidine derivatives were evaluated for their ability to protect macrophages from cell death following infection with Bacillus anthracis, a gram-positive spore-forming bacterium. Four bis-(imidazolinylindole) compounds were identified with potent antibacterial activity as measured by the protection of macrophages and by the inhibition of bacterial growth in vitro. These compounds were effective against a broad range of gram-positive and gram-negative bacterial species, including several antibiotic-resistant strains. Minor structural variations among the four compounds correlated with differences in their effects on bacterial macromolecular synthesis and mechanisms of resistance. In vivo studies revealed protection by two of the compounds of mice lethally infected with B. anthracis, Staphylococcus aureus, or Yersinia pestis. Taken together, these results indicate that the bis-(imidazolinylindole) compounds represent a new chemotype for the development of therapeutics for both gram-positive and gram-negative bacterial species as well as against antibiotic-resistant infections.
authors.affiliation: United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, Frederick, MD 21702-5011, USA. rekha.panchal@amedd.army.mil
authors.forename: Rekha G
authors.initials: RG
authors.lastname: Panchal
authors.forename: Ricky L
authors.initials: RL
authors.lastname: Ulrich
authors.forename: Douglas
authors.initials: D
authors.lastname: Lane
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Butler
authors.forename: Chad
authors.initials: C
authors.lastname: Houseweart
authors.forename: Timothy
authors.initials: T
authors.lastname: Opperman
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.forename: Norton P
authors.initials: NP
authors.lastname: Peet
authors.forename: Donald T
authors.initials: DT
authors.lastname: Moir
authors.forename: Tam
authors.initials: T
authors.lastname: Nguyen
authors.forename: Rick
authors.initials: R
authors.lastname: Gussio
authors.forename: Terry
authors.initials: T
authors.lastname: Bowlin
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D013211:Staphylococcus aureus / Q000187:drug effects; D015010:Yersinia pestis / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents