In vitro characterization of the antibacterial spectrum of novel bacterial type II topoisomerase inhibitors of the aminobenzimidazole class.
Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.
Mani
Nagraj
N
Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA.
Gross
Christian H
CH
Parsons
Jonathan D
JD
Hanzelka
Brian
B
Müh
Ute
U
Mullin
Steve
S
Liao
Yusheng
Y
Grillot
Anne-Laure
AL
Stamos
Dean
D
Charifson
Paul S
PS
Grossman
Trudy H
TH
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D027081:DNA Gyrase; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D059005:Topoisomerase II Inhibitors; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D001798:Blood Proteins; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; C510778:VRT 125853; C510779:VRT 752586; D014508:Urea; D027081:DNA Gyrase