Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi
We investigated the activity of the tuberculosis drug SQ109 against 16 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>C. parapsilosis</i>, <i>C. tropicalis</i>, <i>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<sup>+</sup>/Ca<sup>2+</sup> homeostasis in <i>S. cerevisiae</i> 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.
Authors
- Hoja Patterson
- David S. Perlin (ORCID: https://orcid.org/0000-0002-9503-3184)
- Milena Kordalewska (ORCID: https://orcid.org/0000-0001-8479-0721)
- Carol A. Nacy (ORCID: https://orcid.org/0000-0001-9546-3785)
- Jorge D. Calderin (ORCID: https://orcid.org/0000-0002-9462-6180)
- Akanksha M. Pandey (ORCID: https://orcid.org/0000-0002-8204-9558)
- Rocio Garcia‐Rubio (ORCID: https://orcid.org/0000-0003-4610-2996)
- Luis Ostrosky‐Zeichner (ORCID: https://orcid.org/0000-0002-4784-7589)
- Eric Oldfield (ORCID: https://orcid.org/0000-0002-0996-7352)
- Satish R. Malwal (ORCID: https://orcid.org/0000-0001-7606-1932)
- Rutilio A. Fratti (ORCID: https://orcid.org/0000-0001-9109-6666)
- Erika Shor (ORCID: https://orcid.org/0000-0003-3655-0963)
- Nathan P. Wiederhold (ORCID: https://orcid.org/0000-0002-2225-5122)
- Chi Zhang (ORCID: https://orcid.org/0009-0000-8605-3848)
- Renping Zhou (ORCID: https://orcid.org/0000-0001-6985-6542)
Institutions
- University of Illinois Urbana-Champaign (US)
- The University of Texas at San Antonio Health Science Center (US)
- Georgetown University (US)
- Office of Infectious Diseases (US)
- Sequella (United States) (US)
- Hackensack Meridian Health (US)
- Center for Discovery (US)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1021/acsinfecdis.5c00210
- Citations
- 3
- Primary Topic
- Fungal Biology and Applications
- Type
- article
- Field-Weighted Citation Impact
- 4.18
Funders
- University of Illinois at Urbana-Champaign
- National Institute of Allergy and Infectious Diseases
- Division of Molecular and Cellular Biosciences