TY - JOUR
T1 - Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi
AU - Malwal, Satish R.
AU - Garcia-Rubio, Rocio
AU - Kordalewska, Milena
AU - Patterson, Hoja
AU - Zhang, Chi
AU - Calderin, Jorge D.
AU - Zhou, Ruijie
AU - Pandey, Akanksha M.
AU - Shor, Erika
AU - Perlin, David S.
AU - Wiederhold, Nathan P.
AU - Ostrosky-Zeichner, Luis
AU - Fratti, Rutilio
AU - Nacy, Carol
AU - Oldfield, Eric
N1 - Publisher Copyright:
© 2025 American Chemical Society.
PY - 2025/6/13
Y1 - 2025/6/13
N2 - 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.
AB - 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.
KW - Candida
KW - Histoplasma
KW - antifungals
KW - calcium
KW - protonophore
KW - vacuoles
UR - https://www.scopus.com/pages/publications/105005464496
UR - https://www.scopus.com/pages/publications/105005464496#tab=citedBy
U2 - 10.1021/acsinfecdis.5c00210
DO - 10.1021/acsinfecdis.5c00210
M3 - Article
C2 - 40367247
AN - SCOPUS:105005464496
SN - 2373-8227
VL - 11
SP - 1662
EP - 1672
JO - ACS Infectious Diseases
JF - ACS Infectious Diseases
IS - 6
ER -