Microbial secondary metabolites, now named as specialized metabolites, often have unusual structures and many have demonstrated major effects on the health, nutrition and economics of our society [1]. These compounds are usually low molecular mass products of secondary metabolism, which take place out of step with the main microbial growth phase. They include antibiotics, pigments, toxins, enzyme inhibitors, immunomodulators, effectors of ecological competition or symbiosis, or compounds with hormonal activity or particular effects on lipids or carbohydrates metabolism. Some have already established themselves as antimicrobials, antivirals, antioxidants, antitumorals, vaso-relaxants or contractants, diuretics or laxatives. Others are used as colorants, pesticides, or growth promoters for animals or plants [2]. Approximately 53% of the FDA-approved natural products-based drugs are originating from microorganisms [3].

The synthesis of specialized metabolites is finely adjusted by nutritive sources, growth conditions, feedback control, enzyme induction or inactivation. Their regulation is often influenced by specific low molecular mass compounds, also transfer RNA, σ factors and gene products formed during post-exponential development. Recent research demonstrated that the production of specialized metabolites is mostly coded by clustered genes on chromosomal DNA rather than by plasmidic DNA. However, the related pathways are still not fully clarified and thus provide a new theoretical frontier for academic researchers in enzymology, control and differentiation [4].

Omic sciences such as genomic, transcriptomic or metabolomic applied to industrial microorganisms now offer new opportunities for strain discovery characterization and improvement. Thus, great potential exists for the development of novel compounds for pharmaceutical, nutraceutical, dyeing, or agricultural industries.

Not so long ago, scientists discovered that the marine realm is an incredibly rich biotope for the discovery of new microorganisms and subsequently the characterization of valuable new molecules.

Sponges and their associated microbiota have been found to produce a wide variety of bioactive secondary metabolites. In the pharmaceutical field, several natural products extracted from marine organisms have already demonstrated their capacity to delay aging and/or extend lifespan. However, the biodiversity from the Southwest of the Indian Ocean is much less studied, especially regarding anti-aging activities. In the study presented by Saïd-Hassane et al. (2020) [5], the microbial diversity of the marine sponge Scopalina hapalia was investigated by metagenomic analysis. Twenty-six bacterial and two archaeal phyla were recovered from the sponge, of which the Proteobacteria phylum was the most abundant. Thirty isolates affiliated to the genera Bacillus, Micromonospora, Rhodoccocus, Salinispora, Aspergillus, Chaetomium, Nigrospora and or related to the family Thermoactinomycetaceae were cultivated for secondary metabolites production. Crude extracts from selected microbial cultures were found to be active against elastase, tyrosinase, catalase, sirtuin 1, CDK7 (Cyclin-dependent kinase 7), Fyn kinase and proteasome. These results highlight the potential of microorganisms associated with a marine sponge from the Indian Ocean to produce anti-aging compounds.

Marine epiphytic bacteria are also highly diverse, and ubiquitous in marine biotopes where they have to survive constant pressures coming from physicochemical parameters (hydrostatic pressure, low oxygenation, salinity…), biotic competition or predation (e.g., protozoans and nematodes). These marine organisms have developed defense strategies to face adversity, for example by producing toxic bioactive compounds. Several active metabolites have been identified from these microorganisms coming from specific genes expression. The review of Salikin et al. (2020) [6] focuses on the potential of marine epiphytic bacteria to be a new platform for novel anti-nematode drug development. Emerging strategies, including culture-independent high-throughput screening to discover new strains are highlighted.

The review by Nawaz et al. (2020) [7] focuses on pigments and provides an overview of marine bacteria synthetizing bio-pigments, along with their applications. It highlights a range of molecules already valued at the industrial level such as prodigiosin, astaxanthin, violacein, zeaxanthin, lutein or lycopene.

Insect-associated bacteria, are supposed to be involved in the life cycle of their host due to the panel of secondary metabolites they are able to produce. These strains are certainly one of the less explored sources of new active compounds. With the aim of efficiently discovering new bioactive molecules, the diversification of the culture conditions of one strain may induce the activation of diverse biosynthetic gene clusters. This OSMAC approach (one strain many compounds) is based on the fact that some microbial metabolites are not produced under certain set of physicochemical parameters and may appear when the conditions are modified. Inspired by these two approaches, the production of the cyclic pentapeptides pentaminomycins C, D and E was significantly improved in the culture of the Streptomyces sp. GG23 strain, an actinobacteria isolated from the guts of Tenebrio molitor (the mealworm beetle) [8]. The analysis of the non-ribosomal peptide biosynthetic gene cluster suggested that the unicity of the compounds, based on the structural variations, originates from the low specificity of the adenylation domain in the non-ribosomal peptide synthetase (NRPS) module 1, indicating that macrocyclization can be catalyzed non-canonically by penicillin binding protein (PBP)-type TE. Additionally, pentaminomycins C and D exhibited significant autophagy-inducing activities and were cytoprotective against menadione-induced oxidative stress in vitro.

One original domain of exploration is the analysis of secondary metabolites obtained from microbial co-cultures, via metabolome tools. Among the rich microbiote isolated from the Red Sea sponge Coscinoderma mathewsi (23 isolates), three actinomycetes strains were defined as novel species of the genera Micromonospora, Nocardia, and Gordonia [9]. This study of Shamikh et al. (2020) [9] demonstrated that Micromonospora sp. UA17 co-cultured with two mycolic acid-containing actinomycetes namely Gordonia sp. UA19 and Nocardia sp. UA 23, or supplemented with pure mycolic acid could produce metabolites such as a chlorocardicin, neocopiamycin A, and chicamycin B that were not found in the respective monocultures. This implies a mycolic acid effect on the induction of cryptic natural product biosynthetic pathways and reveals that silent biosynthetic gene clusters can show their unusual capacities for the production of secondary metabolites, under unclassical cultivation conditions.

Siderophores, as serratiochelins, are specialized compounds with high affinity for ferric iron, that are produced by the opportunistic pathogen Serratia marcescens. The siderophores are of pharmaceutical interest as they can be used in their native form to treat iron overload diseases or facilitate uptake of antibiotics by bacteria, through siderophore-antibiotic drug conjugate. In the study of Schneider (2020) [10], the rare siderophore serratiochelin A was extracted with high yields from an iron-depleted co-culture of Serratia sp. and Shewanella sp. (a strain from marine environment also involved in iron cycle). As this molecule was not observed in axenic cultures of Shewanella or Serratia, the co-culturing may induce the production of the compound, possibly because of the competition for iron between the two strains in the culture medium. The serratiochelin A antibacterial effect was tested and was specific towards S. aureus. The molecule also exhibited toxic effects on both eukaryotic cell lines A2058 and MRC5.

Thereafter, the construction of microbe consortia opens up an endless avenue of exploration towards the production of new bioactive molecules.

Streptomyces is a very studied genus, historically known for the production of bioactive compounds. However, strains of unusual origins are able to furnish new natural products. As an example, the Streptomyces sp. strain IB201691-2A from the Lake Baikal endemic mollusk Benedictia baicalensis synthesizes three new angucyclines (baikalomycins A–C), as well as large quantities of rabelomycin and 5-hydroxy-rabelomycin [11]. Baikalomycins A–C exhibited varying levels of anticancer properties. Rabelomycin and 5-hydroxy-rabelomycin also showed antiproliferative activities. The gene cluster for baikalomycins biosynthesis was identified, cloned and expressed in S. albus J1074. Heterologous expression and deletion experiments allowed the glycosyltransferase functions implicated in the synthesis of these original compounds to be specified.

The crude extract from a culture of Curvularia papendorfii, an endophytic fungus isolated from Vernonia amygdalina, a medicinal plant from Sudan, revealed an important antiviral effect against the human coronavirus HCoV 229E and the feline coronavirus FCV F9 [12]. Additionally, a selective antibacterial activity against Staphylococcus sp. was observed, as well as an interesting antiproliferative competence against the human breast carcinoma MCF7 cell line. Twenty-two metabolites were identified from this extract and two major pure compounds were characterized including a new polyhydroxyacid: kheiric acid. Kheiric acid showed effective inhibition capacities against methicillin-resistant Staphylococcus aureus (MRSA). Hence, endophytes merit more attention, as a treasure trove of new bioactive compounds.

Given the societal implications, the search for bioactive properties of bio-based molecules mobilizes considerable energy among research teams.

The marine microalgae Aurantiochytrium sp. is considered a promising source for docosahexaenoic acid (DHA) production. DHA is a n-3 long-chain polyunsaturated fatty acid and is critical for cellular processes involved in maintaining health. In the study of Liu et al. (2020) [13], UV mutagenesis was utilized to obtain competitive Aurantiochytrium sp. strain with enhanced DHA production (1.90-fold higher than wild strain). The key genes related to the increasing DHA accumulation were explored by comparing the transcriptome between the mutant and the parent strain. The mRNA expression levels of CoAT, AT, ER, DH, and MT genes, are linked to the increased intercellular production of DHA, and can be manipulated to control DHA yields in Aurantiochytrium sp. The genetic improvement of microbial strains is thus only at the beginning of its immense possibilities.

Biofilms, composed of microbial secreted exopolysaccharides, protects bacteria against adverse environmental conditions but favor the contamination of surfaces as diverse as foodstuffs or medical material. A classical approach to eliminate biofilms is to use natural anti-microbial compounds. However, new chemical synergies are still emerging, as developed by Argüelles et al. (2020) [14], such as the joint use of carnosic acid (obtained from rosemary) and propolis (from honeybees’ panels), to control the pathogenic yeast Candida albicans. Recent advances in biofilm eradication also involve the intervention of lytic phages. In the study of Papaianni et al. (2020) [15] the lytic activity of Xccφ1 (Xanthomonas campestris pv. campestris-specific phage) was evaluated in combination with 6-pentyl-α-pyrone (a secondary metabolite produced by Trichoderma atroviride P1) associated with hydroxyapatite. The results demonstrated that Xccφ1, alone or in combination with 6PP and HA (φHA6PP complex), interferes with the gene pathways involved in the formation of biofilm, by modulating the genes involved in the biofilm formation and stability (rpf, gumB, clp and manA). This approach can be used as a model to fight against other biofilm-producing bacteria.

With the hypothesis that the use of antimicrobial textiles may significantly reduce the risk of nosocomial infections, Hamed et al. (2020) [16] focused their attention on endophytic fungi isolated from marine organisms, collected from saline environments. The antimicrobial and antioxidant activities of 32 fungal isolates were examined against a panel of pathogenic bacteria and fungi. The ethyl acetate crude extracts of 21 strains initially possessed antimicrobial or antioxidant activities. As an innovation, the surface of cellulosic fabrics was functionalized by grafting of MCT-βCD (monochlorotriazinyl β-cyclodextrin), creating core-shaped hydrophobic cavities. Furthermore, inclusion of the three most active fungal extracts (Aspergillus calidoustus M113, Aspergillus terreus 7S4, Alternaria alternata 13A) into the hydrophobic cavities was achieved. The experience demonstrated that Aspergillus calidoustus strain M113 exhibited the most promising improvement in the antimicrobial functionality, and the second best in the UV protection of this novel generation of fabrics. A low/weak toxicity against normal human skin fibroblasts was determined. Large-scale production of this bioactive extracts as well as the industrial application of the process to develop eco-friendly multifunctional textiles, is the first step to determine the economic feasibility.

Based on in silico techniques that have recently gained attention in drug discovery programs (e.g., structure and ligand-based virtual screening, docking and molecular dynamics), the team of Sayed (2020) worked on the protein Mpro [17]. This important protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key of the viral infection, ensuring the cleavage of the two replicase proteins pp1a and pp1ab. Mpro was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings. The Natural Products Atlas (N. P. Atlas), a data base of more than 24,000 microbial natural compounds, was screened to find out analogues exhibiting antiviral activity, by adapting to the catalytic site of Mpro. Using Lipinski’s rules, 9933 drug-like candidates were detected. Top-scoring hits were further filtered out depending on their ability to show appropriate binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme’s conformers. Six compounds exhibiting high potential as anti-SARS-CoV-2 drug candidates were consequently detected. Further in vitro testing of the selected molecules is a promising starting point for the rapid development of medicament candidates against SARS-CoV-2.