There is an increasing interest in the use of beneficial microorganisms as alternatives to chemically synthesized or plant-derived molecules to produce therapeutic agents. Bacterial endophytes are plant-associated microorganisms that can colonize different parts of living plants without causing any diseases. Diverse endophytic bacteria possess the ability to synthesize a wide range of secondary metabolites with unique chemical structures that have been exploited for their anti-microbial, antiviral, anti-cancer, and anti-inflammatory properties. Additionally, production of these bioactive compounds can also benefit the host plant as they may play a significant role in a plant’s interaction with the environment for adaptation and defense. As a result of their significant impact as curative compounds or as precursors to produce new drugs, the biotechnological possibilities of secondary metabolites derived from endophytic bacteria are immense.

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Secondary Metabolites Produced by Plant Growth-Promoting Bacterial Endophytes

In addition to the typical respiratory manifestations, various disorders including involvement of the nerve system have been detected in COVID-19 ranging from 22 to 36%. Although growing records are focusing on neurological aspects of COVID-19, the pathophysiological mechanisms and related therapeutic methods remain obscure. Considering the increased concerns of SARS-CoV-2 potential for more serious neuroinvasion conditions, the present review attempts to focus on the neuroprotective effects of natural compounds as the principle source of therapeutics inhibiting multiple steps of the SARS-CoV-2 infection cycle. The great majority of the natural products with anti-SARS-CoV-2 activity mainly inhibit the attachment, entry and gene expression rather than the replication, assembly, or release. Although microbial-derived natural products comprise 38.5% of the known natural products with neuroprotective effects following viral infection, the neuroprotective potential of the majority of microorganisms is still undiscovered. Among natural products, chrysin, huperzine A, ginsenoside Rg1, pterostilbene, and terrein have shown potent in vitro neuroprotective activity and can be promising for new or repurpose drugs for neurological complications of SARS-CoV-2. 

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Neurological disorders of COVID-19: insights to applications of natural products from plants and microorganisms

The marine environment presents a favorable avenue for potential therapeutic agents as a reservoir of new bioactive natural products. Due to their numerous potential pharmacological effects, marine-derived natural products—particularly marine peptides—have gained considerable attention. These peptides have shown a broad spectrum of biological functions, such as antimicrobial, antiviral, cytotoxic, immunomodulatory, and analgesic effects. The emergence of new virus strains and viral resistance leads to continuing efforts to develop more effective antiviral drugs. Interestingly, antimicrobial peptides (AMPs) that possess antiviral properties and are alternatively regarded as antiviral peptides (AVPs) demonstrate vast potential as alternative peptide-based drug candidates available for viral infection treatments. Hence, AVPs obtained from various marine organisms have been evaluated. This brief review features recent updates of marine-derived AVPs from 2011 to 2021. Moreover, the biosynthesis of this class of compounds and their possible mechanisms of action are also discussed. Selected peptides from various marine organisms possessing antiviral activities against important human viruses—such as human immunodeficiency viruses, herpes simplex viruses, influenza viruses, hepatitis C virus, and coronaviruses—are highlighted herein.

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Antiviral Peptides (AVPs) of Marine Origin as Propitious Therapeutic Drug Candidates for the Treatment of Human Viruses

Metabolomics is an important emerging field of omics technology. While the metabolic pathways in prokaryotic or disease-causing agents are relatively simple compared to those of mammalian hosts, metabolite pools reflect the instant (snapshot) status of cells under healthy or diseased conditions or when infecting the host (Tan et al., 2007) (Lee et al., 2015). In humans, immune cells play a major role in the defense against microbial infection. The metabolic pathways of immune cells are under the stringent control of metabolites and small molecules under a quiescent or active state. Any subtle change in the gene expression during the diseased condition can affect the downstream pathways that consist of proteins and metabolites. Metabolites belong to different chemical groups such as amino acids, organic acid, lipids, or amines. Due to their close association with the cellular system, the detection of metabolites can provide the accurate status of the cell and can also be used as biomarkers of disease or drug targets (Rahman and Hasan 2014). Considering the importance of the field of metabolomics, the current research topic aimed to collect articles where metabolites and metabolite detection tools are used for different purposes in infectious disease. Articles published in this issue show how metabolomics can be used as biomarkers of disease during pandemics, use of metabolomics in clinical management of infectious disease, during metabolomics coinfection of virus and bacteria, metabolites associated with inflammatory disease, and specific proteins associated with transport molecules during communicable and noncommunicable disease. In this issue, an original research article by Taleb et al. (2021) shows that metabolic changes can be used to predict the recovery pattern in critically ill patients caused by the pandemic strain of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Using targeted metabolomics of serum samples, patients that were admitted within 48 h and were under invasive mechanical ventilation (IMV) in the intensive care unit (ICU) had different levels of hypoxanthine and betaine at the first time point of admission. These levels can predict whether the patient will require a short or long stay in the ICU. Another group of metabolites including kynurenine, 3-methylhistidine, ornithine, p-cresol sulfate, C24, and sphingomyelin was measured 1 week later and these could accurately predict the duration of IMV. Another original research conducted by Elrayees et al. (2022) shows that COVID-19 severity is high in patients with type 2 diabetes mellitus and hypertension. Using tandem mass spectrometry as the analytical platform, targeted metabolomics were conducted in serum samples from patients with different disease severity, diabetes status, and hypertension status. Using multivariate and univariate models for data analysis, the authors showed that patients with diabetes and hypertension had increased severity of COVID-19 and reduced levels of specific triacylglycerols. Edited and reviewed by: Ramcés Falfán-Valencia, Instituto Nacional de Enfermedades Respiratorias-México (INER), Mexico

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Editorial: Metabolomics in Infectious Diseases

Xenobiotic receptors, such as the pregnane X receptor, regulate multiple host physiologic pathways including xenobiotic metabolism, certain aspects of cellular metabolism, and innate immunity. These ligand-dependent nuclear factors regulate gene expression via genomic recognition of specific promoters and transcriptional activation of the gene. Natural or endogenous ligands are not commonly associated with this class of receptors; however, since these receptors are expressed in a cell-type specific manner in the liver and intestines, there has been significant recent effort to characterize microbially derived metabolites as ligands for these receptors. In general, these metabolites are thought to be weak micromolar affinity ligands. This journal anniversary minireview focuses on recent efforts to derive potentially nontoxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic receptor–modifying pathophysiology. The review will include our perspective on the field and recommend certain directions for future research. SIGNIFICANCE STATEMENT Xenobiotic receptors (XRs) regulate host drug metabolism, cellular metabolism, and immunity. Their presence in host intestines allows them to function not only as xenosensors but also as a response to the complex metabolic environment present in the intestines. Specifically, this review focuses on describing microbial metabolite–XR interactions and the translation of these findings toward discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease.

Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

The present global COVID-19 pandemic caused by the noble pleomorphic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a vulnerable situation in the global healthcare and economy. In this pandemic situation, researchers all around the world are trying their level best to find suitable therapeutics from various sources to combat against the SARS-CoV-2. To date, numerous bioactive compounds from different sources have been tested to control many viral diseases. However, microbial metabolites are advantageous for drug development over metabolites from other sources. We herein retrieved and reviewed literatures from PubMed, Scopus and Google relevant to antiviral microbial metabolites by searching with the keywords "antiviral microbial metabolites," "microbial metabolite against virus," "microorganism with antiviral activity," "antiviral medicine from microbial metabolite," "antiviral bacterial metabolites," "antiviral fungal metabolites," "antiviral metabolites from microscopic algae' and so on. For the same purpose, the keywords "microbial metabolites against COVID-19 and SARS-CoV-2" and "plant metabolites against COVID-19 and SARS-CoV-2" were used. Only the full text literatures available in English and pertinent to the topic have been included and those which are not available as full text in English and pertinent to antiviral or anti-SARS-CoV-2 activity were excluded. In this review, we have accumulated microbial metabolites that can be used as antiviral agents against a broad range of viruses including SARS-CoV-2. Based on this concept, we have included 330 antiviral microbial metabolites so far available to date in the data bases and were previously isolated from fungi, bacteria and microalgae. The microbial source, chemical nature, targeted viruses, mechanism of actions and IC50/EC50 values of these metabolites are discussed although mechanisms of actions of many of them are not yet elucidated. Among these antiviral microbial metabolites, some compounds might be very potential against many other viruses including coronaviruses. However, these potential microbial metabolites need further research to be developed as effective antiviral drugs. This paper may provide the scientific community with the possible secret of microbial metabolites that could be an effective source of novel antiviral drugs to fight against many viruses including SARS-CoV-2 as well as the future viral pandemics.

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Puja Roy

Papers

Microbial Metabolites: The Emerging Hotspot of Antiviral Compounds as Potential Candidates to Avert Viral Pandemic Alike COVID-19.