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Fungi are a small but important part of the human microbiota and several fungi are familiar to the immune system, yet certain can cause infections in immunocompromised hosts and referred as opportunistic pathogens. The fungal coinfections in COVID-19 hosts with predisposing conditions and immunosuppressive medications are posing higher severity and death. The immunological counteraction (innate/adaptive immunity) is triggered when the PRRs on the host cells recognize the fungal PAMPs. However, in simultaneous infections (COVID-19 and fungal coinfection), the synergism of TLR and NLR may hyperactivate the immune cells which dramatically increase the cytokine level and generate cytokine storm. Fungal colonization in the human gut assists the development of microbiome assembly, ecology, and shaping immune response. However, SARS-CoV-2 infection represented unstable mycobiomes and long-term dysbiosis in a large proportion in COVID-19 patients. Normally, amphotericin B is considered as first-line treatment for invasive fungal infection. So, amphotericin B therapy is recommended in COVID-19 hosts with serious fungal infections. Still, the long-term corticosteroid supplementation prescribed in case of severe pneumonia and lower oxygen levels may result in systemic fungal infection in COVID-19 patients, eventually limiting the lifesaving benefits of available medications. Also, due to the evolution of fungal resistance to available antibiotics, the current treatments are becoming ineffective. Therefore, this review summarizes the concerns, needed to deal with the impending crises.

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The current study assessed the metabolite abundance, alpha (α)-amylase and α-glucosidase inhibitory, antioxidant, and antibacterial activity of the ethyl acetate extract (EAE) of endophytic Penicillium lanosum (PL) and Penicillium radiatolobatum (PR). A higher extract yield was found in EAE-PR with a total phenolic content of 119.87 ± 3.74 mg of GAE/g DW and a total flavonoid content of 16.26 ± 1.95 mg of QE/g DW. The EAE-PR inhibited α-amylase and scavenged ABTS+ radicals with a half-maximal inhibitory concentration (IC50) of 362.5 and 37.5 µg/mL, respectively. Compared with EAE-PL, EAE-PR exhibited higher antibacterial activity against Gram-positive and Gram-negative pathogens. Treatment with EAE-PR (1000 µg/mL) did not cause significant toxicity in the HEK-293 cell line compared to the control cells (p < 0.05). EAE-PR treatments (250–1000 µg/mL) showed higher cytoprotective effects toward H2O2-stressed HEK-293 cells compared with ascorbic acid (AA). The UHPLC-Q-TOF-MS/MS analysis revealed the presence of thiophene A (C13H8S), limonene (C10H16), and phenylacetic acid (C8H8O2) in EAE-PR. Furthermore, these compounds demonstrated substantial interactions with diabetes (α-amylase and α-glucosidase), oxidative stress (NADPH-oxidase), and bacteria (D-alanine D-alanine ligase)-related enzymes/proteins evidenced in silico molecular docking analysis.