The prevalence and pervasiveness of drug-resistant pathogens create havoc in the health sector by surpassing the exigent issue of microbial infections with increased mortality and morbidity ^[1][2][1,2]. Thus, a dire need of drug discovery and development of novel antibiotics with improved modes of action is required. Natural products are the preeminent storehouse and foundation for drug production [3]. Its putative contribution along with its analogous metabolites (synthetic or combinatorial libraries) toward people’s health has intensified over the years [4]. Bioprospecting of terrestrial biomes have been largely exhausted; thus, a paradigm shift of focus was progressively redirected towards the heterogeneity of marine habitats for natural products [5]. Marine natural products can yield a much greater estimate of potency than its terrestrial counterparts ^[6][7][6,7]. The marine environment is an attractive field of research which continues to receive great attention, as more natural products are being uncovered over the years ^{[8][9][10][11]}[8,9,10,11]. The de-replication strategy of recurrent known compounds has led to the shortage of novel compounds. Strategies taken to address this issue involve screening extreme biomes such as the deep-sea on the premise that extreme abiotic conditions give rise to complex chemistry [12]. Therefore, deep-sea peregrination is diverted from geological and ecological surveys to bioprospecting for natural bioactive compounds [13].

The marine realm is the largest inhabitable space for living biomass, since it encompasses 71% of the earth’s surface with deep-sea area being geographically vast ^[14][15][16][24,25,26]. The deep sea is home to unprecedented and tremendous marine biodiversity, rivalling that of coral reefs and rainforest ^[17][18][27,28]. In tandem with this, it has a water depth of 200 m and beyond and yet remains poorly explored ^[19][29]. The deep-sea biodiversity holds significant economic values and contributes to key ecological processes of the ocean ^[20][21][30,31]. Deep sea is an unique and extreme environment, primarily due to the documented characteristics: (1) elevated hydrostatic pressure; (2) low levels of oxygen capacity or anoxia; (3) temperature drops to abyssal values; and (4) decline of light intensity or photons ^[14][22][24,32]. These challenging conditions hone its inhabitant’s biology through mutation of gene expressions and primary and secondary metabolite pathways, which enables them to thrive and survive ^[23][33].

The deep sea comprises a collection of heterogeneous habitats including abyssal plain, hydrothermal vents, continental margins, cold water corals, seamounts, hadal zone, and oxygen minimum zones that nest numerous life forms ^[24][34]. Although the deep-sea area is geographically greater, the census of deep-sea prokaryote is meager ^[15][25]. The uncharted territories of deep sea have made them potential reservoirs of specialized metabolites and curiosity destinations for bioprospecting ^[25][35]. Limitations in research capabilities and resources during the past have hindered and set constrains on sourcing marine organisms at depths unreachable by scuba ^[26][36]. However, the advent and introduction of sophisticated ocean technologies such as remotely operated vehicles (ROVs) and submersible technology have unlocked new opportunities for bioprospecting programs; thus, deep-sea bioprospecting have become more accessible and feasible with continuous upgrades of these technologies ^[27][28][37,38]. Of all the known marine natural products, 2% circa is derived from the deep-sea environment ^[17][27]. Deep-sea-derived natural products have various biological activities such as antiviral, antibacterial, antifungal, anti-inflammatory, insecticidal, and antitumor ^{[17][18][25][29][30][31]}[27,28,35,39,40,41]. More than 70% of deep-sea natural products are biologically active ^[32][42]. Despite the ubiquity of microbial richness, most indigenous marine microbes remain uncultured due to limited knowledge about their physiology and environmental interactions ^[33][34][43,44]. Thus, endeavors to devise specific strategies in overcoming the technological as well as the culturing barrier are relevant despite its chronological challenges ^{[24][30][35][36]}[21,34,40,45]. The percentage of undiscovered species from the deep ocean is higher, relatively awaiting description ^[37][46]. In this context, access to deep sea brings with it the potential to discover valuable and beneficial compounds. Microorganisms undebatably dominate the Earth’s land and ocean masses ^[38][47]. The deep-sea microbes engage in complex and undeciphered interspecies interactions which boost their fitness ^[39][48].

Actinomycetes are highly evolved and well-suited to thrive in deep-sea extremities. They are multifarious and sophistically equipped with an impressive array of unique molecular and chemical scaffolds deemed to be exquisite and complex ^[40][49]. The particularity and complexity of deep-sea habitats forces actinomycetes to exhibit a remarkable adaptation strategy due to their genomic evolution, which brings about unique physiology and metabolism ^[41][50]. Higher diversity of microorganisms including actinomycete genera occurs at greater depth (>1000 m) ^[42][43][51,52]. Generally, the distribution and composition of marine actinobacteria is dependent on the physicochemical parameters including pressure, pH, temperature, salinity, and total organic carbon across sparse locations ^[44][53]. Marine actinobacteria, including those thriving in deep-sea habitats occupy a multitude of habitats, either as a symbiont in invertebrates such corals, sponge, and other marine organisms or as ecosystem engineer responsible for the turnover of complex molecules, contributing to biogeochemical cycles ^[44][45][53,55], across various deep-sea ecosystems such as the water columns (warm/cold water currents), the ocean bed or sedimentary mats, and hydrothermal vents. However, the trace of deep-sea actinobacteria is abundant in deep-sea sediments ^[46][54].

The deep-sea actinomycetes are capable of producing bioactive compounds. In recent years, an inventory of studies revealed that deep-sea actinomycetes occupy a spectrum of interesting metabolites ^[35][47][21,56]. Natural compounds recovered from terrestrial and marine environments are specific to each environment with specific margins of similarity. Studies have suggested that although deep-sea are part of the marine environment, it may well represent a separate and unique ecosystem that harbors actinomycetes with enhanced bioactivity. [5]. To highlight, a study by ^[48][57] analyzed the antimicrobial activity of tunicamycins from the deep-sea-derived Streptomyces xinghaiensis SCSIO S15077. Interesting results showed that tunicamycins were reported for the first time to be effective against Bacillus thuringiensis, Candida albicans CMCC (F) 98001, and Candida albicans ATCC 96901. Another study by ^[49][58] highlighted the anticancer effects of cyclic dipeptides and phenolic compounds from the deep-sea derived Streptomyces xiamenensis MCCC 1A01570 due to their ability to influence the transcription activation function of retinoid X receptor-α (RXRα). Additionally, deep-sea sediment-derived Streptomyces sp. YB104 is considered to produce relatively large quantities of inthomycin B (a bioactive compound with antimicrobial, herbicidal, and anticancer properties) production compared to other species in industrial settings ^[50][59]. A wealth of natural products derived from deep-sea actinomycetes are proven to be effective and therefore be considered for further pharmaceutical development.

Metagenomic research with DNA extraction of microorganisms have revolutionized the bioprospecting strategy ^[51][60]. Studies have substantially revealed that microbes genetically encode their natural products in biosynthetic gene clusters (BGCs). A BGC can be defined as a physically clustered group of two or more genes in a particular genome that together encode a biosynthetic pathway for the production of a specialized metabolite (including its chemical variants) ^[52][61]. Different structural classes of BGCs exist, including non-ribosomal peptide synthetases (NRPS), polyketide synthases (PKS), terpenes, and bacteriocins. NRPS and PKS are popular targets for natural product discovery, as they are known to synthesize a diversity of antibiotics and immunosuppressants with enormous pharmaceutical potential ^{[53][54][55][56]}[62,63,64,65]. The number of BGCs is species-dependent, but individual BGCs has a family of cognate compounds that share a core with a variety in substituents ^[57][66]. Each strain of actinomycetes genome on average contains 30–40 secondary metabolism biosynthetic gene clusters, and yet most of which are cryptic ^[58][67]. For instance, Streptomyces genus is the largest natural producer of bioactive compounds ^[59][17], and its genome contains 25–70 BGCs, most of which are cryptic and are not expressed under normal laboratory conditions ^[60][61][68,69]. Doroghazi et al. ^[60][68] did an extensive comparative study by analyzing the genomes of six actinomycetes genera, namely Mycobacterium, Corynebacterium, Rhodococcus, Arthrobacter, Frankia, and Streptomyces, in detail to determine the extent to which natural product gene clusters are conserved within each genus. They showed that within the immense gene clusters diversity, there are patterns showing that some genera have higher prevalence of NRPS or PKS natural products compared to other genera. For example, some groups found conservation of the spore pigment and desferrioxamine class of siderophores in Streptomyces, along with mycolic acid, mycobactin and phthiocerol in Mycobacterium. Further, Hifnawy et al. ^[62][70] discuss in their review that the genus Micromonospora is a model system for natural product research. Using biosynthetic gene clusters and gene cluster families from 87 Micromonospora genomes, they showed that this genus contains 2387 BGCs that could be grouped into 1033 BGC-families. The majority of BGC-families belong to the type 1 polyketide synthases (T1PKS) and the non-ribosomal peptide synthetases (NRPS) ^[62][70]. This highlights the immense potential that the actinobacteria phylum possesses.

Nonetheless, there are available molecular tools designated for the genetic engineering of actinomyces in order to harvest their valuable compounds ^[63][71]. Apart from that, the functions of genome mining have complemented the classical chemistry-driven screening ^[64][72]. A study by ^[65][73] indicated that Streptomyces koyangensis SCSIO 5802 produces two active metabolites. However, the analysis of its complete genome revealed its potential to produce 21 categories of natural products. Another study ^[66][74] unveiled 37 putative BGCs of deep-sea-derived Streptomyces olivaceus SCSIO T05. Attempts to activate the cryptic BGCs resulted in the discovery of a known compound, lobophorin CR4 (antibacterial and antitumor properties). The genomic data of Janibacter limosus, a deep-sea actinobacterium, revealed a gene cluster for degrading phenol and its derivatives ^[67][75]. Two deep-sea Streptomyces isolates (MA3_2.13 and S07_1.15) have 32 and 24 BGCs, respectively. About 30 percent of the characterized BGCs have gene homologies with known clusters of compounds previously described ^[68][76]. Genome mining of the deep-sea-derived Streptomyces atratus SCSIO ZH16 leads to the activation of a cyclodepsipeptide gene cluster and the recovery of a potent compound known as atratumycin, which has antibacterial activity ^[69][77]. Branchybacterium ginsengisoli B129SM11, an actinobacterium isolated from a deep-sea sponge, is capable of producing enzyme that degrades polyethylene terephthalate (PET). The functions of genome sequencing coupled with genome mining identifies an encoded putative PET hydrolase gene that produces a polyesterase-type enzyme tagged as BgP ^[70][78]. Additionally, the complete sequenced genome of Mycetocola spongiae MSC19^T has 2887 coding sequences which harbor genes for heavy metal resistance, natural product synthesis and multidrug resistance ^[71][79]. The sequencing of deep-sea actinomycete whole genomes magnifies their biosynthetic potential for producing pharmaceutical metabolites.

An impressive yield of novel species and compounds from deep-sea actinomycetes was found between 2016 and 2022. A few of the novel species of actinobacteria described were further evaluated for their diverse innate potentials. To illustrate, Micromonospora provocatoris harbors n-acetylgutaminyl glutamine amide and deferoxamine B ^[72][80]. Kocuria oceani has the ability to reduce iron (III) in both aqueous and solid forms ^[73][81]. Micromonospora ferruginea has the capacity to produce natural products such as kosinostatin and isoquinocycline B, which exhibit both antibiotic and antitumor properties ^[74][82]. The novel compounds discovered belong to various chemical classes, and most of them yield bioactive properties with different modes of action such as cytotoxic activity, anti-allergic activity, antifungal activity, antibacterial activity, and antiviral activity.

From the 101 compounds discovered, 40 of them have no visibility of biological activity against the numerous cancer cell lines and pathogenic test strains. For instance, 3R-OH-1,6-diene-cyclohexylacetic acid, linear tetradepsipeptide, N1-N5-di-p-(EE)-coumaroyl-N10-acetylsepermidine, and furan fatty acid are compounds produced by Agrococcus sp. SCSIO 52902 from a deep-sea sediment that display no cytotoxic activity against human tumor cell lines (A-549, HL-60, and HCT-116) and no antibacterial activity against Gram-positive and Gram-negative bacteria ^[75][83]. However, 39 compounds reported have a vivid trace of potency either against specific human cancer cell lines, pathogenic fungal strain and both Gram-positive and Gram-negative bacteria. For example, paulomycin G is a compound produced by Micromonospora matsunotoense M-412 that displays a strong cytotoxic activity against tumor cell lines of pancreatic adenocarcinoma, breast adenocarcinoma and hepatocellular carcinoma ^[76][84]. Interestingly, Actinomadura sp. KD439 is reported to harbor potent compounds such as kumemicinones A-G, which are cytotoxic against P388 murine leukemia cells ^[77][85]. Selective compounds such as streptothiazolidine A, streptodiketopiperazine A and B, and (S)-1-(3-ethylphenyl)-1,2-ethanediol belonging to Streptomyces sp. SY1965 were reported to have antifungal effect towards Candida albicans ^[78][86]. Further, nocardiopsistins A−C derived from Nocardiopsis sp. HB-J378 have a cytotoxic activity against methicillin-resistant Staphylococcus aureus ^[79][87]. Apart from that, a collection of novel compounds, i.e., amycolachromones A−F (Amycolatopsis sp. WP1) ^[80][88] and georgenione A (Georgenia sp. 40DY180) ^[81][89], display weak inhibitory activity against the ABH2 enzyme and anti-tyrosinase activity against tyrosinase enzyme, respectively. Moreover, 14 of the total novel compounds were reported with no bioactive analyses. These compounds are produced by various deep-sea actinomycetes such as Streptomyces sp. SCSIO ZS0520 (actinopyrones E-G, seco-salinomycins A-E and minipyrone) ^[82][83][90,91], Micromonospora echinospora SCSIO 04089 (nenestatin B) ^[84][92], Dermacoccus abyssi MT1.1 (dermacozine M) ^[85][93], Streptomyces olivaceus SCSIO T05 (olimycin A and B) ^[86][94], and Williamsia sp. MCCC 1A11233 (3-benzyl-3α,4β-dihydroxypentan-2-one) ^[87][95]. Additionally, albisporachelin is a compound isolated from Amycolatopsis albisporachelin WP1T, which functions as a chelating agent for coordinating iron update ^[88][96]. From the inventory of species from which the new compounds are discovered, the genus Streptomyces is frequent. Overall, new species and compounds of actinomycetes are being discovered on a constant basis, as studies multiply in that environment.