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Repurposing an inhibitor of ribosomal biogenesis with broad anti-fungal activity.

ABSTRACT: The lack of new antifungal compounds with unique mechanisms of action is a concern for therapeutic management of patients. To identify inhibitors against human pathogenic fungi, we screened ~3000 compounds provided by the Developmental Therapeutics Program of NIH/NCI against a panel of pathogenic fungi including Candida species, Aspergillus fumigatus, and Cryptococcus neoformans. NSC319726 (a thiosemicarbazone) had broad antifungal activity in the range of 0.1-2.0?µg/ml and was also inhibitory to fluconazole-resistant isolates of Candida species. Synergy was demonstrated with NSC319726 and azoles, as well as caspofungin. The inhibitory concentration 50% (IC50) of NSC319726 was 35-800-fold higher than the Minimum Inhibitory Concentration 50% (MIC50 values), which indicates low compound toxicity to human cells in vitro. Transcriptome analysis of treated and untreated C. albicans using Gene Ontology (GO) revealed a large cluster of down regulated genes that encode translational proteins, especially those with ribosome biogenesis functions. As NSC319726 was first shown to have anti-cancer activity, its affects against human pathogenic fungi establish NSC319726 as a repurposed, off-patent compound that has potential antifungal activity. The minimal in vitro toxicity of lead optimized NSC319726 and its reasonable inhibitory activity against pathogens suggest advancing this compound to in vivo toxicity testing and protection studies against candidiasis.

SUBMITTER: Sun N

PROVIDER: S-EPMC5717060 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Repurposing an inhibitor of ribosomal biogenesis with broad anti-fungal activity.

Sun Nuo N Li Dongmei D Zhang Yuhan Y Killeen Kyle K Groutas William W Calderone Richard R

Scientific reports 20171205 1

The lack of new antifungal compounds with unique mechanisms of action is a concern for therapeutic management of patients. To identify inhibitors against human pathogenic fungi, we screened ~3000 compounds provided by the Developmental Therapeutics Program of NIH/NCI against a panel of pathogenic fungi including Candida species, Aspergillus fumigatus, and Cryptococcus neoformans. NSC319726 (a thiosemicarbazone) had broad antifungal activity in the range of 0.1-2.0 µg/ml and was also inhibitory t ...[more]

PMID: 29209049

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Project description:ObjectiveThe fungal unfolded protein response consists of a two-component relay in which the ER-bound sensor, IreA, splices and activates the mRNA of the transcription factor, HacA. Previously, we demonstrated that hacA is essential for Aspergillus fumigatus virulence in a murine model of fungal keratitis (FK), suggesting the pathway could serve as a therapeutic target. Here we investigate the antifungal properties of known inhibitors of the mammalian Ire1 protein both in vitro and in a treatment model of FK.MethodsThe antifungal activity of Ire1 inhibitors was tested against conidia of several A. fumigatus isolates by a microbroth dilution assay and against fungal biofilm by XTT reduction. The influence of 4μ8C on hacA mRNA splicing in A. fumigatus was assessed through gel electrophoresis and qRT-PCR of UPR regulatory genes. The toxicity and antifungal profile of 4μ8C in the cornea was assessed by applying drops to uninfected or A. fumigatus-infected corneas 3 times daily starting 4 hours post-inoculation. Corneas were evaluated daily through slit-lamp imaging and optical coherence tomography, or at endpoint through histology or fungal burden quantification via colony forming units.ResultsAmong six Ire1 inhibitors screened, the endonuclease inhibitor 4μ8C displayed the strongest antifungal profile with an apparent fungicidal action. The compound both blocked conidial germination and hyphal metabolism of A. fumigatus Af293 in the same concentration range that blocked hacA splicing and UPR gene induction (60-120 μM). Topical treatment of sham-inoculated corneas with 0.5 and 2.5 mM 4μ8C did not impact corneal clarity, but did transiently inhibit epithelialization of corneal ulcers. Relative to vehicle-treated Af293-infected corneas, treatment with 0.5 and 2.5 mM drug resulted in a 50% and >90% reduction in fungal load, respectively, the latter of which corresponded to an absence of clinical signs of infection or corneal pathology.ConclusionThe in vitro data suggest that 4μ8C displays antifungal activity against A. fumigatus through the specific inhibition of IreA. Topical application of the compound to the murine cornea can furthermore block the establishment of infection, suggesting this class of drugs can be developed as novel antifungals that improve visual outcomes in FK patients.

Project description:Lipopeptide-19, a HIV fusion inhibitor (LP-19), has showed potent anti-HIV activity. However, there is still limited information of the antiviral activity against different subtype clinical isolates and the drug resistance barrier of LP-19. Therefore, 47 HIV clinical isolates were selected for this study. The viral features were identified, in which 43 strains are CCR5 tropisms, and 4 strains are CCR5/CXCR4 tropisms, and there are 6 subtype B', 15 CRF01_AE, 14 CRF07_BC, 2 CRF08_BC and 10 URF strains. These 47 viruses were used to detected and analyze the inhibitory activities of LP-19. The results showed that the average 50% inhibitory concentration (IC50) and 90% inhibitory concentration (IC90) of LP-19 were 0.50 nM and 1.88 nM, respectively. The average IC50 of LP-19 to B', CRF01_AE, CRF07_BC, CRF08_BC, and URF strains was 0.76 nM, 0.29 nM, 0.38 nM, 0.85 nM, and 0.44 nM, respectively. C34 and Enfuvirtide (T-20), two fusion inhibitors, were compared on the corresponding strains simultaneously. The antiviral activity of LP-19 was 16.7-fold and 86-fold higher than that of C34 and T-20. The antiviral activity of LP-19, C34, and T-20 were further detected and showed IC50 was 0.15 nM, 1.02 nM, and 66.19 nM, respectively. IC50 of LP-19 was about 7-fold and 441-fold higher compared to C34 and T-20 against HIV-1 NL4-3 strains. NL4-3 strains were exposed to increasing concentrations of LP-19 and C34 in MT-2 cell culture. The culture virus was sequenced and analyzed. The results showed that A243V mutation site identified at weeks 28, 32, 38, and 39 of the cell culture in the gp41 CP (cytoplasmic domain) region. NL4-3/A243V viruses containing A243V mutation were constructed. Comparing the antiviral activities of LP-19 against HIV NL4-3 to HIV strains (only 1.3-fold), HIV did not show drug resistance when LP-19 reached 512-fold of the initial concentration under the drug pressure for 39 weeks. This study suggests that LP-19 has broad-spectrum anti-HIV activity, and high drug resistance barrier.

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Repurposing an inhibitor of ribosomal biogenesis with broad anti-fungal activity.

Publications

Repurposing an inhibitor of ribosomal biogenesis with broad anti-fungal activity.

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