title: Symmetric bis-benzimidazoles are potent anti-staphylococcal agents with dual inhibitory mechanisms against DNA gyrase.
abstract: Various bis-benzimidazole derivatives have been reported to possess activity against Gram-positive pathogens. No mechanism of action has been elucidated to fully account for the antibacterial activity of this class of compounds. A group of symmetric bis-benzimidazoles (BBZ) designed as anticancer agents have previously been shown to possess moderate antiproliferative activity. We sought to assess the antibacterial activity and mechanism of action of BBZ compounds against Staphylococcus aureus. Antibacterial activities were assessed by determination of minimal inhibitory concentrations (MICs), time-kill curves, and scanning electron microscopy. Transcriptional responses to BBZ treatment were determined using whole genome microarrays. Activities against bacterial type II topoisomerases were investigated using in vitro supercoiling, decatenation, DNA binding, and DNA cleavage inhibition assays. MICs for EMRSA-16 were between 0.03 and 0.5 μg/mL. The compounds showed concentration-dependent bactericidal activity and induced cell swelling and lysis. Transcriptional responses to BBZ were consistent with topoisomerase inhibition and DNA damage. A subset of BBZ compounds inhibited S. aureus DNA gyrase supercoiling activity with IC(50) values in the range of 5-10 μM. This inhibition was subsequently shown to operate through both inhibition of binding of DNA gyrase to DNA and accumulation of single-stranded DNA breaks. We conclude that BBZ compounds are potent anti-staphylococcal agents and operate at least in part through DNA gyrase inhibition, leading to the accumulation of single-stranded DNA breaks, and by preventing the binding of gyrase to DNA.
authors: UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
authors: Aaron G
authors: AG
authors: Dale
authors: Jason
authors: J
authors: Hinds
authors: John
authors: J
authors: Mann
authors: Peter W
authors: PW
authors: Taylor
authors: Stephen
authors: S
authors: Neidle
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D027081:DNA Gyrase / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000201:enzymology; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology*; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D004269:DNA, Bacterial; D059005:Topoisomerase II Inhibitors; C009712:bis-benzimidazole; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase