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Frediansyah, A.;  Sofyantoro, F.;  Alhumaid, S.;  Mutair, A.A.;  Albayat, H.;  Altaweil, H.I.;  Alafghani, H.M.;  Alramadhan, A.A.;  Alghazal, M.R.;  Turkistani, S.A.; et al. Microbial Natural Products and COVID-19 Infection. Encyclopedia. Available online: https://encyclopedia.pub/entry/25125 (accessed on 18 July 2025).
Frediansyah A,  Sofyantoro F,  Alhumaid S,  Mutair AA,  Albayat H,  Altaweil HI, et al. Microbial Natural Products and COVID-19 Infection. Encyclopedia. Available at: https://encyclopedia.pub/entry/25125. Accessed July 18, 2025.
Frediansyah, Andri, Fajar Sofyantoro, Saad Alhumaid, Abbas Al Mutair, Hawra Albayat, Hayyan I. Altaweil, Hani Mohammad Alafghani, Abdullah A. Alramadhan, Mariam R. Alghazal, Safaa A. Turkistani, et al. "Microbial Natural Products and COVID-19 Infection" Encyclopedia, https://encyclopedia.pub/entry/25125 (accessed July 18, 2025).
Frediansyah, A.,  Sofyantoro, F.,  Alhumaid, S.,  Mutair, A.A.,  Albayat, H.,  Altaweil, H.I.,  Alafghani, H.M.,  Alramadhan, A.A.,  Alghazal, M.R.,  Turkistani, S.A.,  Abuzaid, A.A., & Rabaan, A. (2022, July 14). Microbial Natural Products and COVID-19 Infection. In Encyclopedia. https://encyclopedia.pub/entry/25125
Frediansyah, Andri, et al. "Microbial Natural Products and COVID-19 Infection." Encyclopedia. Web. 14 July, 2022.
Microbial Natural Products and COVID-19 Infection
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This entry is adapted from the peer-reviewed paper 10.3390/molecules27134305

The SARS-CoV-2 virus, which caused the COVID-19 infection, was discovered two and a half years ago. It caused a global pandemic, resulting in millions of deaths and substantial damage to the worldwide economy. Only a few vaccines and antiviral drugs are available to combat SARS-CoV-2. However, there has been an increase in virus-related research, including exploring new drugs and their repurposing. Since discovering penicillin, natural products, particularly those derived from microbes, have been viewed as an abundant source of lead compounds for drug discovery. 

natural products SARS-CoV-2 COVID-19 influenza RSV

1. Anti-Influenza

The flu is a contagious respiratory illness caused by influenza viruses that infiltrate the nose, throat, and lungs. It can cause mild to severe illness and even death. Symptoms include fever, cough, sore throat, headache, fatigue, vomiting, and diarrhea. Human influenza A causes seasonal flu and has become a worldwide epidemic flu disease. This virus is classified into several subtypes based on the proteins on the virus’s surface layer known as hemagglutinin (H) and neuraminidase (N) [1]. Scientists have recently discovered 18 hemagglutinin subtypes (H1 to H18) and 11 neuraminidase subtypes (N1 to N11) [2]. H1N1 and H3N2 are the most common subtypes of influenza A circulating in humans [3]. The vaccine against influenza A is commercially available and protects against influenza viruses. It has been determined that the antiviral medications umifenevir and arbidol are effective in treating influenza A. These nucleoside antiviral drugs are directed toward the hemagglutinin envelope glycoprotein as their primary target [4]. Oseltamivir, also known as Tamiflu, is an additional medication that inhibits the neuraminidase of the influenza virus [4].
Spirostaphylotrichin X is a novel spirocyclic lactam isolated from the marine fungus Cochliobolus lunatus SCSIO41401 [5]. Spirostaphylotrichin X, with an IC50 value of 1.2 to 5.5 μM, demonstrated vigorous inhibitory activity against various influenza virus strains [5]. According to the mechanism of action, spirostaphylotrichin X inhibits influenza A virus replication by interfering with the activity of the PB2 protein [5]. In addition, the hybrid polyketide known as cladosin C, which was isolated from the deep-sea fungus Cladosporium sphaerospermum 2005-01-E3, contains a novel linear 6-enamino-7(8)-en-10-ol moiety with anti-influenza activity [6]. Furthermore, a marine actinobacterium known as Verrucosispora sp. MS100137 was responsible for the production of abyssomicin Y [7]. It is an abyssomicin of type I, and it has an epoxide group attached to the 8th and 9th carbon atoms in the structure. On oatmeal agar, Verrucosispora sp. was isolated from the sediment collected in April 2010 from a depth of 2733 m below sea level in the South China Sea, at the coordinates 20 degrees 9.795 inches north and 118 degrees 18.124 degrees east [7]. Abyssomicin Y has an IC50 of 8 μg/mL for anti-influenza A activity in A549 cells; however, ribavirin, a positive control drug, has only an IC50 of > 16 μg/mL.
In addition to marine fungi, extremophiles, such as acidophilic fungi, are a significant source of bioactive compounds and a potentially useful source of new anti-influenza medications. Purpurquinone B and C, purpurester A, and TAN-931 were isolated from the ethyl acetate extract of an acid-tolerant fungus Penicillium purpurogenum JS03-21 [8]. These compounds showed significant antiviral activity against H1N1, with IC50 values of 61.3, 64.0, 85.3, and 58.6 μM, respectively [8]. The mangrove-associated fungus Diaporthe sp. (SCSIO 41011) synthesized pestalotiopsone B and F, as well as 3,8-dihydroxy-6-methyl-9-oxo-9H-xanthene-1-carboxylate and 5-chloroisorotiorin all demonstrated significant anti-IAV activity against three different influenza A virus subtypes, including A/Puerto Rico/8/34 H274Y (H1N1), A/FM-1/1/47 (H1N1), and A/Aichi/2/68 (H3N2), with IC50 values of 2.52-39.97μM [9]. In addition, the aciduric fungal strain known as Penicillium camemberti OUCMDZ-1492 was isolated from an acidic marine niche, mangrove soil and mud, all of which were located close to the roots of Rhizophora apiculate [10]. Three indole-diterpenoids that had been previously isolated, including (2S,4bR,6aS,12bS,12cS,14aS)-3-deoxo-4b-deoxypaxilline, (2S,4aR,4bR,6aS,12bS,12cS,14aS)-4a-demethylpaspaline-4a-carboxylic acid, (2S,3R,4R,4aS,4bR,6aS,12bS,12cS,14aS)-4a-demethylpaspaline-3,4,4a-triol, in addition to two recently isolated indole-diterpenoids, including (2R,4bS,6aS,12bS,12cR,14aS)-9,10-diisopentenylpaxilline and (6S,7R,10E,14E)-16-(1H-indol-3-yl)-2,6,10,14-tetramethylhexadeca-2,10,14-triene-6,7-diol; and emindole SB, 21-isopentenylpaxilline, paspaline, and paxilline, were isolated from its fermentation broth at pH 5.0. These compounds demonstrated significant activity against the H1N1 virus, with IC50 values of 28.3, 38.9, 32.2, 73.3, 34.1, 26.2 μM, respectively [10]. The findings show that 3-oxo, 4-b-hydroxy, and 9-isopentenyl substitutions improve hexacyclic indole-diterpenoids’ anti-H1N1 activity [10]. Furthermore, the mangrove-derived fungus Cladosporium sp. PJX-41 produced molecules with anti H1N1, with IC50 values ranging from 82 to 89 μM, including (14S)-oxoglyantrypine, norquinadoline A, and four known alkaloid derivatives including deoxynortryptoquivaline, deoxytryptoquivaline, tryptoquivaline, and quinadoline B [11].

2. Anti-Respiratory Syncytial Virus

Respiratory syncytial virus, also known as RSV, is a member of the family paramyxoviridae and is a leading viral pathogen associated with the lower respiratory tract. RSV infections typically occur in infants and children worldwide [12]. Because it is a viral respiratory infection, it is the second leading cause of death overall [13]. This virus has also been connected to respiratory illnesses affecting the elderly and people with compromised immune systems. Most people experience a flu-like illness with a mild course as their primary manifestation. In severe cases, it can contribute to the development of bronchiolitis, also known as inflammation of the small lung airways, and pneumonia in children [14]. Two medications that are effective in treating RSV are palivizumab [15], and an aerosol form of ribavirin [16]. However, its application is restricted because it is toxic, expensive, and has highly variable efficacy. From the marine fungus Aspergillus sp strain XS-2009, Chen and his research groups isolated two natural products, namely 22-O-(N-Me-l-valyl)-21-epi-aflaquinolone B and aflaquinolones D, both of which have excellent anti-RSV activity in vitro; their IC50 values are 0.042 and 6.6 μM, respectively [17].

3. Anti-SARS-CoV-2

As of May 2022, the SARS-CoV-2 virus has infected over 510 million of people and killed over 6 million [18]. It has also wreaked havoc on the global economy and healthcare system [19]. Common symptoms of SARS-CoV-2 infection include headaches, fevers, fatigue, dry cough, dyspnea, diarrhea, chest pain, and muscle aches [20][21]. Moreover, some people experience anosmia and dysgeusia [22], as well as hemorrhagic and ischemic strokes [23].
As the pandemic continues, the availability of numerous efficient and safe vaccines has provided some relief [24][25][26]. A long list of potential COVID-19 drug candidates, each with their own mechanism of action, has been proposed [4][27][28][29]. Nevertheless, the US Food and Drug Administration has only approved two antiviral drugs for SARS-CoV-2, including remdesivir, a protease inhibitor, and baricitinib, a Janus kinase inhibitor that inhibits immune system overstimulation [30]. Remdesivir has the potential to be used to treat COVID-19 in both adults and children. In contrast, baricitinib treats COVID-19 in hospitalized adults who require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation [30][31]. However, the WHO only recommends baricitinib as a COVID-19 treatment [31]. Sotrovimab, a monoclonal antibody drug, has also been conditionally approved by the WHO to treat mild to moderate COVID-19 in patients at risk of hospitalization [31]. In spite of these encouraging developments, the development of additional therapeutics, such as small molecules, is necessary for controlling virus transmission and treating patients. A therapeutic approach that has proven effective against human viruses, including SARS-CoV-2, is the use of candidate molecules in combination regimens.
Given the slow rate of new compound discovery and development, repurposing or repositioning natural products to develop antiviral drug-inspired natural products against SARS-CoV-2 infection is becoming a more appealing proposition due to the use of well-characterized low-risk molecules, which may result in lower overall development costs and shorter development timelines.
A recent study published in 2022 found that the antimicrobial natural product aurasperone, isolated from Aspergillus niger in the Red Sea tunicate Phallusia nigra, was highly effective against SARS-CoV-2 in vitro, with an IC50 of 12.25 μM. The IC50 result was comparable to the IC50 of the positive control remdesivir, which was 10.11 μM [32]. The in silico analysis revealed that the molecule aurasperone A targets Mpro in SARS-CoV-2 [32]. Furthermore, neoechinulin A isolated from Aspergillus fumigatus MR2012 from the Red Sea exhibited an IC50 value of 0.47 μM against SARS-CoV-2, with a similar target to Mpro [33]. NeoB, an anti-HBV alkaloid isolated from A. amstelodami, also demonstrated anti-SARS-CoV-2 activity, inhibiting liver X receptors [34]. It has a cytotoxicity threshold (CC50) of greater than 70 μM and an IC50 of 32.9 μM [34]. Furthermore, aspulvinone D, M, and R produced by Cladosporium sp. (7951) have IC50 values of 10.3; 9.4; and 7.7 μM, respectively, for inhibiting SARS-CoV-2 Mpro. Previously, the fungus was isolated from Paris polyphylla var. yunnanensis, a medicinal plant collected in Kunming, China [35].
In addition, virtual screening and docking studies in aspergilol H, arisugacin A, aspernolide A, altertoxin V, cytochalasin Z8, (14S)-oxoglyantrypine, norquinadoline A, deoxynortryptoquivaline, and quinadoline B displayed a relatively high affinity to PLpro, 3CLpro, RNA-dependent RNA polymerase (RdRp), nsp15, and spike protein with binding energy ranging from −6.5 to −10 kcal/mol. Moreover, similar studies showed that 11a-dehydroxyisoterreulactone A displayed a relatively high affinity with 3CLpro of SARS-CoV-2, with a binding energy of -8.9 kcal/mol. Furthermore, isobutyrolactone and aspernolide A bind to Mpro of SARS-CoV-2 via a critical hydrogen bond interaction with Gly143 and Thr415, respectively [36]. RdRP of SARS-CoV-2 showed that alternariol and alternariol-(9)-methyl ether have binding energies of −7.6 and −8.5 kcal/mol, respectively [37]. A similar study of an anti-HSV cyclic peptide, aspergillipeptide D, revealed inhibitory activity against SARS-CoV-2, with Mpro as a target [38]. It then inspired the synthesis and development of five oxazole-based macrocycles with inhibitory activity against SARS-CoV-2 (NRC-03-nhCoV) in Vero-E6 cells, with an IC50 of 18.3–63.3 μM [38].

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Subjects: Respiratory System; Infectious Diseases
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Andri Frediansyah
,
Fajar Sofyantoro
,
Saad Alhumaid
,
Abbas Al Mutair
,
Hawra Albayat
,
Hayyan I. Altaweil
,
Hani Mohammad Alafghani
,
Abdullah A. AlRamadhan
,
Mariam R. AlGhazal
,
Safaa A. Turkistani
,
Abdulmonem A. Abuzaid
,
Ali Rabaan
View Times: 679
Revisions: 2 times (View History)
Update Date: 14 Jul 2022
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