ACS infectious diseases · 2025
Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi.
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Malwal Satish R, Garcia-Rubio Rocio, Kordalewska Milena, Patterson Hoja, Zhang Chi, Calderin Jorge D, Zhou Ruijie, Pandey Akanksha M, Shor Erika, Perlin David S, Wiederhold Nathan P, Ostrosky-Zeichner Luis, Fratti Rutilio, Nacy Carol, Oldfield Eric
Аннотация
We investigated the activity of the tuberculosis drug SQ109 against 16 fungal pathogens: Candida albicans, C. auris, C. glabrata, C. guilliermondi, C. kefyr, C. krusei, C. lusitaniae, C. parapsilosis, C. tropicalis, Cryptococcus neoformans, Rhizopus spp., Mucor spp., Fusarium spp., Coccidioides spp., Histoplasma capsulatum and Aspergillus fumigatus. MIC values varied widely (125 ng/mL to >64 μg/mL) but in many cases we found promising (MIC ∼ 4 μg/mL) activity as well as MFC/MIC ratios of ∼ 2. SQ109 metabolites were inactive. The activity of 12 analogs of SQ109 against Saccharomyces cerevisiae correlated with protonophore uncoupling activity, suggesting mitochondrial targeting, consistent with the observation that growth inhibition was rescued by agents which inhibit ROS species accumulation. SQ109 disrupted H+/Ca2+ homeostasis in S. cerevisiae vacuoles, and there was synergy (FICI ∼ 0.26) with pitavastatin, indicating involvement of isoprenoid biosynthesis pathway inhibition. SQ109 is, therefore, a potential antifungal agent with multitarget activity.