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In vitro and in vivo efficacy of the antimycobacterial molecule SQ109 against the human pathogenic fungus, Cryptococcus neoformans

ABSTRACT: Cryptococcosis is an opportunistic fungal infection affecting individuals with compromised immunity, particularly those with HIV. The limited accessibility to effective treatments, emerging resistance to current antifungals, and treatment-related toxicities underline the pressing need for more effective therapeutic options. In this study, we conducted a whole-cell screening of ~ 3,700 FDA-approved drugs and clinical molecules against the Cryptococcus neoformans H99 strain to identify potential antifungal candidates. The anti-mycobacterial agent SQ109 was identified as one of the most potent hits, with broad antifungal activity. SQ109 exhibited potent activity against Cryptococcus spp., with an MIC90 of 4 μg/mL. In the time-kill assay, SQ109 demonstrated fungicidal activity against proliferating cryptococcal cells in a concentration-dependent manner. Unlike fluconazole (FLC) and flucytosine (5-FC), C. neoformans showed minimal tendency to develop resistance to SQ109 during frequent passaging. Furthermore, SQ109 exhibited a potent efficiency in the murine model of cryptococcal infection, resulting in a 50% survival rate among the group treated with 25 mg/kg for 10 consecutive days. The transcriptomic analysis revealed that SQ109 disrupts ergosterol biosynthesis, affecting membrane integrity and oxidative stress homeostasis, which aligns with its interaction with other ergosterol pathway inhibitors, including FLC. Additionally, molecular docking and structural analysis indicated that squalene synthase protein ERG9 is the most likely target of SQ109 within the ergosterol biosynthesis machinery of cryptococcal cells. These findings highlight the therapeutic potential of SQ109 in combating cryptococcal infections, both as a standalone therapy and as an adjuvant to FLC monotherapy.

ORGANISM(S): Cryptococcus neoformans H99

PROVIDER: GSE299869 | GEO | 2025/06/16

REPOSITORIES: GEO

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Project description:A family of APSES transcription factor is known to be fungal-specific transcriptional regulators and play important roles in governing growth, differentiation, and virulence of diverse fungal pathogens. Yet none of APSES-like transcription factors have been identified and investigated in a basidiomycetous fungal pathogen, Cryptococcus neoformans. In the present study we discovered an APSES-like transcription factor, Msa1 (Mbp1/Swi4-like APSES protein 1), as one of novel flucytosine-responsive genes (total 194 genes) identified through comparative transcriptome analysis of C. neoformans hybrid sensor kinase mutants, tco1 and tco2 mutants, which displayed differential flucytosine-susceptibility. Supporting the microarray data, Northern blot and quantitative RT-PCR analysis confirmed that expression of MSA1 is rapidly induced in response to flucytosine in the wild-type strain, but not in the tco1 and tco2 mutants. Furthermore, C. neoformans with deletion of the MSA1 gene exhibited increased susceptibility to flucytosine. Intriguingly, Msa1 plays pleiotropic roles in diverse cellular process of C. neoformans. Msa1 positively regulates ergosterol biosynthesis and thereby its inhibition confers increased susceptibility and resistance to amphotericin B and azole drugs, respectively. Msa1 is also involved in DNA damage repair counteracting genotoxic stresses. During sexual differentiation Msa1 represses pheromone production, but promotes cell-cell fusion. Furthermore Msa1 is required for production of antioxidant melanin pigment and full virulence of C. neoformans. Finally we also performed DNA microarrray analysis to identify Msa1-regulated genes in C. neoformans. A majority of them were found to be involved in cell cycle regulation and DNA repair. Therefore, this study provides a novel antifungal therapeutic method for treatment of cryptococcosis. There are more than 95% of genome homology between JEC21 and H99. Therefore 24 slides of JEC21 (cryptococcus neoformans var. neoformans serotype D) 70-mer oligo are used in this analysis, 3 biological replicate experiments are performed, total RNAs are extracted under 2 conditions (with or without treatment of Flucytosine) with 4 strains from H99 (H99 Wild type strain (Cryptococcus neoformans var. grubii serotype A), tco1Δ , tco2Δ , skn7Δ), We use the mixed all of total RNAs from this experiment as a control RNA. We use Cy5 as Sample dye and Cy3 as a control dye.

Project description:A family of APSES transcription factor is known to be fungal-specific transcriptional regulators and play important roles in governing growth, differentiation, and virulence of diverse fungal pathogens. Yet none of APSES-like transcription factors have been identified and investigated in a basidiomycetous fungal pathogen, Cryptococcus neoformans. In the present study we discovered an APSES-like transcription factor, mbs1 (Mbp1/Swi4-like APSES protein 1), as one of novel flucytosine-responsive genes (total 194 genes) identified through comparative transcriptome analysis of C. neoformans hybrid sensor kinase mutants, tco1 and tco2 mutants, which displayed differential flucytosine-susceptibility. Supporting the microarray data, Northern blot and quantitative RT-PCR analysis confirmed that expression of mbs1 is rapidly induced in response to flucytosine in the wild-type strain, but not in the tco1 and tco2 mutants. Furthermore, C. neoformans with deletion of the mbs1 gene exhibited increased susceptibility to flucytosine. Intriguingly, mbs1 plays pleiotropic roles in diverse cellular process of C. neoformans. mbs1 positively regulates ergosterol biosynthesis and thereby its inhibition confers increased susceptibility and resistance to amphotericin B and azole drugs, respectively. mbs1 is also involved in DNA damage repair counteracting genotoxic stresses. During sexual differentiation mbs1 represses pheromone production, but promotes cell-cell fusion. Furthermore mbs1 is required for production of antioxidant melanin pigment and full virulence of C. neoformans. Finally we also performed DNA microarrray analysis to identify mbs1-regulated genes in C. neoformans. A majority of them were found to be involved in cell cycle regulation and DNA repair. Therefore, this study provides a novel antifungal therapeutic method for treatment of cryptococcosis. total RNAs are extracted 2 strains from H99 (H99 Wild type strain (Cryptococcus neoformans var. grubii serotype A), mbs1Δ), We use the mixed all of total RNAs from this experiment as a control RNA. We use Cy5 as Sample dye and Cy3 as a control dye.

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In vitro and in vivo efficacy of the antimycobacterial molecule SQ109 against the human pathogenic fungus, Cryptococcus neoformans

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