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In vitro and in vivo efficacy of the antimycobacterial molecule SQ109 against the human pathogenic fungus, Cryptococcus neoformans

Summary

Researchers discovered that SQ109, an antimycobacterial drug, can effectively kill Cryptococcus fungi that cause serious brain infections in people with weakened immune systems. Unlike current treatments, cryptococcal cells don’t easily develop resistance to SQ109, and it works even better when combined with fluconazole. In mouse studies, SQ109 successfully treated cryptococcal infections, suggesting it could be a valuable new treatment option for patients worldwide, especially in resource-limited regions.

Background

Cryptococcosis is an opportunistic fungal infection affecting immunocompromised individuals, particularly those with HIV, with mortality rates exceeding 60%. Current treatment options are limited to three systemic antifungals with accessibility issues and treatment-related toxicities. The need for more effective therapeutic options remains pressing.

Objective

To identify and evaluate novel antifungal agents against Cryptococcus neoformans through screening of FDA-approved drugs and clinical molecules. To characterize the mechanism of action and therapeutic potential of SQ109 as a novel antifungal agent.

Results

SQ109 demonstrated potent fungicidal activity against Cryptococcus species with MIC90 of 4 μg/mL and negligible resistance development. Transcriptomic analysis and molecular docking identified squalene synthase (ERG9) as the primary target, disrupting ergosterol biosynthesis. SQ109 achieved 50% survival rate in mice treated with 25 mg/kg and showed synergistic activity with fluconazole.

Conclusion

SQ109 exhibits significant therapeutic potential against cryptococcal infections as both a standalone therapy and adjuvant to fluconazole. Its favorable pharmacokinetic properties, low resistance development, and in vivo efficacy support clinical development for treating cryptococcal meningitis.
  • Published in:PLoS Neglected Tropical Diseases,
  • Study Type:Experimental Study,
  • Source: PMID: 41401231, DOI: 10.1371/journal.pntd.0013837
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