The cyclin dependent kinase (CDK)7 inhibitor BS-181 inhibits pathogenic Cryptococcus species, causing G<sub>2</sub>/M arrest and a splicing defect.
BS-181 shows potential antifungal activity against Cryptococcus species and may enhance the efficacy of amphotericin B, but further research is needed to confirm these findings in human populations.
Where it sits
this study against the rest of the pramlintide corpusSummary and findings
This study investigates the antifungal activity of the cyclin dependent kinase (CDK)7 inhibitor BS-181 against Cryptococcus species. The study reports that BS-181 inhibits the growth of Cryptococcus neoformans and Cryptococcus gattii, showing synergy with amphotericin B. The findings suggest potential repurposing of CDK7 inhibitors for fungal infections.
Abstract
The fungal priority pathogen and basidiomycete, <i>Cryptococcus neoformans (Cn)</i>, causes lung and brain infection in predominantly immuno-compromised individuals and there is an urgent need for new treatment options. The pyrazolopyrimidine-based cyclin dependent kinase (CDK)7 inhibitor, BS-181, has anticancer properties, but its antifungal activity has not been investigated. We show that cryptococcal CDK7 more closely resembles the human enzyme than that of ascomycetes, and that BS-181 inhibits its activity. BS-181 inhibited growth of both <i>Cn</i> and <i>Cryptococcus gattii</i> (<i>Cg</i>), but not ascomycete fungi and delayed progression through the G<sub>2</sub>/M phase of the cell cycle. Transcriptomic analysis revealed that BS-181 induces splicing defects leading to elevated intron retention within the transcriptome and also suppresses translational processes. BS-181 displayed additive or synergistic activity with licensed antifungals against laboratory and clinical <i>Cn</i> and <i>Cg</i> strains, most notably with amphotericin B where synergy (2-4-fold reduction in the amphotericin B MIC) was achieved using low-sub micromolar concentrations of BS-181. Compared with either drug alone, BS-181-AmB combination therapy provided greater protection against <i>Cn</i> infection in a wax moth model (<i>p</i> ≤ 0.032) and extended survival of <i>Cn</i>-infected mice. These findings demonstrate that CDK7 inhibitors, already of interest as anticancer agents, could be repurposed to prevent or treat opportunistic fungal infections in cancer patients when combined with licensed antifungals limited by either toxicity or resistance.
Background
The study addresses the urgent need for new treatment options for infections caused by Cryptococcus neoformans, particularly in immunocompromised individuals. Previous research has established the pathogenicity of Cryptococcus species, but the antifungal potential of CDK7 inhibitors like BS-181 had not been explored. This study is significant as it investigates a novel approach to combat these infections using existing anticancer agents.
Methods
The study employed laboratory and clinical strains of Cryptococcus neoformans and Cryptococcus gattii to assess the antifungal activity of BS-181. The primary outcomes included growth inhibition and the minimum inhibitory concentration (MIC) of amphotericin B in combination with BS-181. The study also utilized a wax moth model and mice to evaluate the therapeutic effects in vivo.
Results
BS-181 inhibited the growth of both Cryptococcus neoformans and Cryptococcus gattii, with a reported 2-4-fold reduction in the MIC of amphotericin B when combined with BS-181. The combination therapy provided greater protection against Cryptococcus neoformans infection in a wax moth model, with a statistical significance of p≤0.032, and extended survival in infected mice.
Interpretation
While the study presents promising results regarding the antifungal activity of BS-181, the effect sizes observed may not translate into clinically meaningful outcomes in humans. The reliance on animal models introduces confounding factors, and the potential for translation to human treatment remains uncertain. Additionally, the study does not provide long-term follow-up data to assess durability of the effects.
Key findings
- 2-4-fold reduction in the amphotericin B MIC with BS-181 at low-sub micromolar concentrations.
- Greater protection against Cryptococcus neoformans infection in a wax moth model, p≤0.032.
- Extended survival of Cryptococcus neoformans-infected mice with BS-181-AmB combination therapy.
Limitations
- Primarily animal models used, limiting human applicability.
- Not reported in abstract for long-term follow-up data.
- Small sample sizes in animal studies may affect generalizability.
- Potential for confounding factors in in vivo models.