Search

Antiretroviral treatment has significantly reduced human immunodeficiency virus infection and mortality. However, the current treatment regimen is limited by adverse side effects, the emergence of drug resistance, and the inability to eliminate viral reservoirs. Here, fifteen endophytic fungi were isolated from Sclerocarya birrea and Hypoxis plants. Crude extracts of Alternaria alternata (strain ID PO4PR1, PO4PR2, and PO2PL1) of the fifteen isolate’s crude extracts showed anti-HIV-1 activity in TZM-bl cell line at inhibitory concentration (IC50) values ranging from 0.017 to 1.170 μg/ml. The three crude extracts also maintained the virus replication inhibition profile on PBMCs and CD4+ T cells at concentrations ranging from 0.3 to 50.2 ng/ml. Partial purification using the solid phase extraction and analysis with Gas Chromatography-Mass spectrophotometry showed a diverse profile. The bioactive compounds were identified based on peak area, retention time, similarity index. The major compounds from GC-MS analysis of A. Alternata revealed the existence of cyclotrisiloxane octamethyl (22.92%); Propaninitrile (16,67%); Pyrrolol[1,2-a]pyrazine-1,4-dione, hexahydro-3-(2-methyl propyl) (10.42%); Silane, diethylethoxy(2-ethoxyethyloxy) (4.17%); Coumarin, 3,4-dihydro-4,5,7-trimethyl- 4,5,7-Trimethyl-2-chromanone (13.7%) and 1,2-Cyclobutanedicarbonitrile (2.08%) with previously reported biological activities such as antimicrobial, anti-inflammatory and antioxidant properties. Therefore, these bioactive compounds from A. alternata fungal endophytes could be repurposed as potential anti-HIV agents. This study showed the potential of endophytic fungi, Alternaria alternata from S. birrea, and Hypoxis species as producers of anti-HIV compounds.

The discovery of silent biosynthetic gene clusters (BGCs) in fungi provides unlimited prospects to harness the secondary metabolites encoded by gene clusters for various applications, including pharmaceuticals. Amplifying these prospects is the new interest in exploring fungi living in the extremes, such as those associated with plants (fungal endophytes). Fungal species in endosymbiosis relationship with plants are recognized as the future factories of clinically relevant agents since discovering that they can produce similar metabolites as their plant host. The endophytes produce these compounds in natural environments as a defense mechanism against pathogens that infect the plant host or as a strategy for mitigating competitors. The signaling cascades leading to the expression of silent biosynthetic gene clusters in the natural environment remain unknown. Lack of knowledge on regulatory circuits of biosynthetic gene clusters limits the ability to exploit them in the laboratory. They are often silent and require tailor-designed strategies for activation. Epigenetic modification using small molecular compounds that alter the chromatin network, leading to the changes in secondary metabolites profile, has achieved considerable success. This review aims to comprehensively analyze the secondary metabolite profiles expressed after treatment with various epigenetic modifiers. We first describe the regulatory circuits governing the expression of secondary metabolites in fungi. Following this, we provide a detailed review of the small molecular modifiers, their mechanism(s) of action, and the diverse chemistries resulting from epigenetic modification. We further show that genetic deletion or epigenetic inhibition of histone deacetylases does not always lead to the overexpression or induction of silent secondary metabolites. Instead, the response is more complex and often leads to differential expression of secondary metabolites. Finally, we propose using this strategy as an initial screening tool to dereplicate promising fungal species.