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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.
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Synthesis and Antibacterial Activity of Ficuseptine and Its Derivatives: Determination of Structure–Activity Relationships
Abstract The indolizinium natural product ficuseptine, produced by the tropical fig tree Ficus septica, has been reported to have antibacterial properties. Herein, the synthesis of ficuseptine, ten analogues with differing aryl substituents, and two aryl regioisomers is reported. Despite several previous total syntheses, synthetically prepared ficuseptine has not been subjected to biological testing to confirm its activity. In our hands, ficuseptine was moderately active in Gram-positive B. spizizenii, with an MIC of 32 μg/mL, which was maintained for most aryl substituents. The position of the aryl rings was crucial, however, since regioisomeric ficuseptine analogues, mimicking related natural products, were found to be inactive. Finally, all ficuseptine derivatives were inactive (MIC >128 μg/mL) against Gram-negative E. coli. Understanding these structure–activity relationships (SAR) is helpful for future studies to understand the molecule’s mechanism of action or further develop its antibacterial properties.
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- Award ID(s):
- 2320384
- PAR ID:
- 10612313
- Publisher / Repository:
- Thieme
- Date Published:
- Journal Name:
- Synlett
- Volume:
- 36
- Issue:
- 08
- ISSN:
- 0936-5214
- Page Range / eLocation ID:
- 1049-1053
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1055/a-2490-2986
