Activities of the Novel Bacterial Topoisomerase Inhibitor OSUAB-0284 against the Biothreat Pathogen Bacillus anthracis and Its Type II Topoisomerases.

Bacillus anthracis is the etiological agent of anthrax and is classified as a Tier 1 biothreat pathogen. The fluoroquinolone ciprofloxacin is a preferred prophylactic drug for potential anthrax infections and acts by stabilizing DNA strand breaks formed by the bacterial type II topoisomerases, gyrase and topoisomerase IV. Unfortunately, widespread fluoroquinolone usage has increased levels of resistance in common bacterial pathogens, raising concern that resistant B. anthracis strains could be misused. Therefore, there is great interest in developing new classes of antibacterials that are efficacious against both wild-type and fluoroquinolone-resistant B. anthracis infections. Previous studies have demonstrated that gepotidacin, a triazaacenaphthylene antibacterial that targets gyrase and topoisomerase IV, displays potent activity against B. anthracis and was efficacious in a rabbit inhalation anthrax model. Given these promising results, we evaluated the activity of OSUAB-0284, a Novel Bacterial Topoisomerase Inhibitor (NBTI) that shares a general pharmacophore with gepotidacin, against B. anthracis. OSUAB-0284 displayed activity against B. anthracis that was comparable to or better than gepotidacin. Both compounds displayed activity against fluoroquinolone-resistant cells. Gepotidacin and OSUAB-0284 increased levels of gyrase- and topoisomerase IV-mediated DNA single-stranded breaks and inhibited the overall catalytic activity of the two enzymes. Both compounds were also more potent than ciprofloxacin against wild-type gyrase and topoisomerase IV and maintained activity against fluoroquinolone-resistant enzymes. Finally, OSUAB-0284 displayed efficacy in a mouse model of inhalation anthrax. These results provide mechanistic underpinnings supporting the use of gepotidacin and OSUAB-0284 against B. anthracis and suggest that they may be potential candidates for the treatment of anthrax.