An official website of the United States government
From a library of compounds, 11 hit antibacterial agents have been identified as potent anti-Gram-positive bacterial agents. These pyrazole derivatives are active against two groups of pathogens, staphylococci and enterococci, with minimum inhibitory concentration (MIC) values as low as 0.78 μg/mL. These potent compounds showed bactericidal action, and some were effective at inhibiting and eradicating Staphylococcus aureus and Enterococcus faecalis biofilms. Real-time biofilm inhibition by the potent compounds was studied, by using Bioscreen C. These lead compounds were also very potent against S. aureus persisters as compared to controls, gentamycin and vancomycin. In multiple passage studies, bacteria developed little resistance to these compounds (no more than 2 × MIC). The plausible mode of action of the lead compounds is the permeabilization of the cell membrane determined by flow cytometry and protein leakage assays. With the detailed antimicrobial studies, both in planktonic and biofilm contexts, some of these potent compounds have the potential for further antimicrobial drug development.
more »
« less
This content will become publicly available on June 13, 2026
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: 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.
more »
« less
- Award ID(s):
- 2216742
- PAR ID:
- 10609152
- Publisher / Repository:
- ACS
- Date Published:
- Journal Name:
- ACS Infectious Diseases
- Volume:
- 11
- Issue:
- 6
- ISSN:
- 2373-8227
- Page Range / eLocation ID:
- 1662 to 1672
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
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.more » « less
-
Little is known concerning terpenoids produced by members of the fungal order Ophiostomales, with the member Harringtonia lauricola having the unique lifestyle of being a beetle symbiont but potentially devastating tree pathogen. Nine known terpenoids, including six labdane diterpenoids (1–6) and three hopane triterpenes (7–9), were isolated from H. lauricola ethyl acetate (EtOAc) extracts for the first time. All compounds were tested for various in vitro bioactivities. Six compounds, 2, 4, 5, 6, 7, and 9, are described functionally. Compounds 2, 4, 5, and 9 expressed potent antiproliferative activity against the MCF-7, HepG2 and A549 cancer cell lines, with half-maximal inhibitory concentrations (IC50s) ~12.54–26.06 μM. Antimicrobial activity bioassays revealed that compounds 4, 5, and 9 exhibited substantial effects against Gram-negative bacteria (Escherichia coli and Ralstonia solanacearum) with minimum inhibitory concentration (MIC) values between 3.13 and 12.50 μg/mL. Little activity was seen towards Gram-positive bacteria for any of the compounds, whereas compounds 2, 4, 7, and 9 expressed antifungal activities (Fusarium oxysporum) with MIC values ranging from 6.25 to 25.00 μg/mL. Compounds 4, 5, and 9 also displayed free radical scavenging abilities towards 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide (O2−), with IC50 values of compounds 2, 4, and 6 ~3.45–14.04 μg/mL and 22.87–53.31 μg/mL towards DPPH and O2−, respectively. These data provide an insight into the biopharmaceutical potential of terpenoids from this group of fungal insect symbionts and plant pathogens.more » « less
-
null (Ed.)ABSTRACT The ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to Gram-negative bacteria was investigated. Its MIC towards Escherichia coli , including β-lactamase expressing Ambler classes A, B, and D, was 8 to 16 μg/ml. Addition of 8 times the MIC of V-r to E. coli was acutely bactericidal and associated with a low frequency of resistance (<2.32 × 10 −10 ). In vivo , V-r markedly reduced E. coli burden by >7 log 10 CFU/g in a thigh muscle model. These data warrant further development of V-r in combatting E. coli , including resistant forms.more » « less
-
Abstract Zinc oxide nanoparticles (ZnO NPs) are versatile and promising, with diverse applications in environmental remediation, nanomedicine, cancer treatment, and drug delivery. In this study, ZnO NPs were synthesized utilizing extracts derived fromAcacia catechu, Artemisia vulgaris, andCynodon dactylon. The synthesized ZnO NPs showed an Ultraviolet–visible spectrum at 370 nm, and X-ray diffraction analysis indicated the hexagonal wurtzite framework with the average crystallite size of 15.07 nm, 16.98 nm, and 18.97 nm for nanoparticles synthesized utilizingA. catechu, A. vulgaris,andC. dactylonrespectively. Scanning electron microscopy (SEM) demonstrated spherical surface morphology with average diameters of 18.5 nm, 17.82 nm, and 17.83 nm for ZnO NPs prepared fromA. catechu, A. vulgaris, andC. dactylon,respectively. Furthermore, ZnO NPs tested againstStaphylococcus aureus, Kocuria rhizophila, Klebsiella pneumonia,andShigella sonneidemonstrated a zone of inhibition of 8 to 14 mm. The cell viability and cytotoxicity effects of ZnO NPs were studied on NIH-3T3 mouse fibroblast cells treated with different concentrations (5 μg/mL, 10 μg/mL, and 50 μg/mL). The results showed biocompatibility of all samples, except with higher doses causing cell death. In conclusion, the ZnO NPs synthesized through plant-mediated technique showed promise for potential utilization in various biomedical applications in the future.more » « less
