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Loss of the Aspergillus fumigatus spindle assembly checkpoint components, SldA or SldB, generates triazole heteroresistant conidial populations

Summary

This research reveals that disabling certain cell division checkpoint proteins in the fungus Aspergillus fumigatus creates populations resistant to triazole antifungal drugs. The resistant fungal cells appear to have abnormal amounts of genetic material, suggesting that loss of these checkpoint controls allows cells with extra chromosomes to survive drug exposure. This discovery provides new insight into how dangerous fungal infections can develop resistance to our most important antifungal treatments.

Background

Aspergillus fumigatus is the leading cause of invasive fungal infections in immunocompromised patients. Triazole antifungals are the primary therapeutic option for treating invasive aspergillosis, but resistance to this drug class has emerged globally and threatens treatment efficacy. The mechanisms underlying triazole resistance acquisition in A. fumigatus remain poorly understood.

Objective

To identify novel signaling pathways regulating triazole susceptibility in A. fumigatus by screening a protein kinase disruption library. To investigate the role of spindle assembly checkpoint components SldA and SldB in antifungal resistance.

Results

Loss of SldA or SldB resulted in heteroresistance to multiple triazoles and ergosterol biosynthesis inhibitors but not to amphotericin B or other stress-inducing compounds. Mutant strains exhibited increased susceptibility to benomyl, indicative of conserved SAC function. Flow cytometry revealed increased mean genome size in ΔsldA and ΔsldB conidia, suggesting aneuploidy development.

Conclusion

Spindle assembly checkpoint components SldA and SldB maintain susceptibility to ergosterol biosynthesis inhibitors in A. fumigatus. Loss of these checkpoint components generates heteroresistant populations, likely through aneuploidy-mediated mechanisms, suggesting a novel link between mitotic fidelity and triazole resistance acquisition.
  • Published in:Microbiology Spectrum,
  • Study Type:Experimental/Laboratory Study,
  • Source: 40522092
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