Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi

We investigated the activity of the tuberculosis drug SQ109 against sixteen fungal pathogens: <i>Candida albicans</i>, <i>C. auris</i>, <i>C. glabrata</i>, <i>C. guilliermondi</i>, <i>C. kefyr</i>, <i>C. krusei</i>, <i>C. lusitaniae</i>, <i>Candida parapsilosis</i>, <i>C. tropicalis, Cryptococcus neoformans</i>, <i>Rhizopus</i> spp., <i>Mucor</i> spp., <i>Fusarium</i> spp., <i>Coccidioides</i> spp., <i>Histoplasma capsulatum</i> and <i>Aspergillus fumigatus</i>. 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 <i>Saccharomyces cerevisiae</i> 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 <i>S. cerevisiae</i> vacuoles, and there was synergy (FICI~0.31) with pitavastatin, indicating involvement of isoprenoid biosynthesis pathway inhibition. SQ109 is, therefore, a potential antifungal agent with multi-target activity.