Evaluation of In Vitro Efficiency of Ciclopirox Against Yersinia pestis and Francisella tularensis

<i>Yersinia pestis</i> and <i>Francisella tularensis</i> are Tier-1 pathogens with high interest for biodefense and public health. Evaluating the antibacterial activity of repurposed drugs against these high-priority pathogens is a key element in the ongoing effort to develop diversified antimicrobial strategies. Drug repurposing offers a cost-effective and time-efficient approach to address antibiotic resistance by identifying new applications for existing therapeutics. In this study, we demonstrate in vitro antibacterial effect of the antifungal agent ciclopirox and offer this drug as a potential antibacterial treatment. Ciclopirox in vitro activity was previously reported against various Gram-negative bacteria, including resistant strains, primarily through iron chelation that disrupts key metabolic pathways and virulence mechanisms. Additionally, it exhibits antibiofilm activity and can potentiate the efficacy of certain antibiotics. Our findings reveal that ciclopirox effectively inhibits the in vitro growth of fully virulent strains of <i>Y. pestis</i> and <i>F. tularensis</i>, as well as avirulent isolates, including avirulent mutants that their wild-type susceptibility was reduced through selection to MIC levels defining them as "nonsusceptible" to ciprofloxacin (<i>Y. pestis</i> Kim53Δ70Δ10 and <i>F. tularensis</i> LVS) and doxycycline (LVS), or resistant to doxycycline (Kim53Δ70Δ10) according to CLSI interpretive criteria. Additionally, prolonged exposure of <i>Y. pestis</i> and <i>F. tularensis</i> to sub-MIC and MIC concentrations of ciclopirox did not lead to an increase in observed MIC during the study period. These results highlight ciclopirox as a potential candidate for treatment alternative, combined with other antibiotic substances or repurposed drugs against these bacterial threats.