Extreme Environment Streptomyces: Potential Sources for New Antibacterial and Anticancer Drug Leads?

Antimicrobial resistance (AR) is recognized as one of the greatest threats to public health and in global concern. Consequently, the increased morbidity and mortality, which are associated with multidrug resistance bacteria, urgently require the discovery of novel and more efficient drugs. Conversely, cancer is a growing complex human disease that demands new drugs with no or fewer side effects. Most of the drugs currently used in the health care systems were of Streptomyces origin or their synthetic forms. Natural product researches from Streptomyces have been genuinely spectacular over the recent years from extreme environments. It is because of technical advances in isolation, fermentation, spectroscopy, and genomic studies which led to the efficient recovering of Streptomyces and their new chemical compounds with distinct activities. Expanding the use of the last line of antibiotics and demand for new drugs will continue to play an essential role for the potent Streptomyces from previously unexplored environmental sources. In this context, deep-sea, desert, cryo, and volcanic environments have proven to be a unique habitat of more extreme, and of their adaptation to extreme living, environments attribute to novel antibiotics. Extreme Streptomyces have been an excellent source of a new class of compounds which include alkaloids, angucycline, macrolide, and peptides. This review covers novel drug leads with antibacterial and cytotoxic activities isolated from deep-sea, desert, cryo, and volcanic environment Streptomyces from 2009 to 2019. The structure and chemical classes of the compounds, their relevant bioactivities, and the sources of organisms are presented.


Introduction
Streptomyces are Gram-positive and have high G + C DNA content with a complex life cycle having the potential to produce many clinically important bioactive molecules. Among Gram-positive bacteria, Streptomyces represents a significant source for supplying bioactive natural products with clinical and pharmaceutical applications. Notably, Streptomyces accounts for 39% of all microbial metabolites, and in Streptomycetales class, this genus alone reported to produce nearly 80% of bioactive molecules [1]. For the genus environments as a source of new bioactive molecules [7][8][9]. Considering this, in recent years, much of the attention focused on more extreme environment habitats such as deep-sea, desert, cryo, and volcanic environments for the isolation of potential Streptomyces species. Until recently, most of the compounds from genus Streptomyces have been isolated by culture-dependent methods rather than by the metagenomic approach. e culture-dependent approach has been demonstrated to have convincing reasons to study the species behaviour and to use many strategically correct procedures such as one strain many compounds (OSMAC) [10] to isolate novel compounds. us, it is the hope that cultivation-based approaches would expand our knowledge in an unprecedented way for the new drug development, genome study, and combinatorial biosynthesis. As evidenced above, Streptomyces is an undoubtedly potent genus to hunt for novel pharmaceutically essential compounds derived from underexplored extreme environment habitats for next-generation drugs to counteract the worldwide increase of drug resistance and to meet the demand for novel drugs with no or fewer side effects.

Deep Sea
Marine ecosystem so far is the most significant known environment on this planet [11]. Of the total marine ecosystem, more than 90% is designated as deep sea characterised with many distinct features [12] that attributed for individual species distribution [13] and an important resource for bioactive molecule discovery. e ocean covers 70% of the total world's surface, and the majority of it is below 1000 meters of depth [14]. It has been documented that the world's ocean contained 16 trenches which are having a depth deeper than 7000 m (submarine_ topographical_features#List_of_oceanic_trenches).
Deep-sea oceans are the most extreme environments on Earth. Skropeta [14] reported that deep sea is the place with the highest richness in biodiversity, surpassing the rain forests and the coral reef. Organisms inhabiting in the deep sea can cope with such harsh conditions in the absence of light and under low percentage of oxygen and extremely high pressures, requiring several adaptations in terms of biochemical and physiological processes [14]. ese special environment variables may lead to producing distinct chemical entities with diverse biological activities. e first article which emphasises on the isolation of natural compound from deep-sea-derived Streptomyces (DSDS) was published in 1995 [15]. After that, this environment was abandoned for nearly a decade. However, since late 2005, the exploration of deep-sea Streptomyces has been steadily growing on. ough the number of publications in connection with deep-sea Streptomyces-derived natural compounds has not been in more significant numbers, emphasis on structural diversity and biological activity made it a crucial extreme habitat to pursue this resource for novel compounds to meet the need of the 21st century. Indeed, it is beyond our expectations even more that actinomycetes have been isolated from Mariana trench, at 10,898 m [7].

Desert
Remarkably, one-fifth of our planet Earth is covered by desert which has been emphasised by devoid of vegetation or low and extremely low and unpredictable rainfall [16]. Desert is further characterised by arid conditions including high UV radiation, extreme temperatures and desiccation, high salinity, the presence of inorganic oxidants, deficient concentrations of organic carbon, and physical instability caused by strong winds [17][18][19]. It has been proposed that the Atacama is the oldest and driest known desert among others on the Earth and as an accurate analogue of Martian soils [20]. Unlike deep-sea environments, desert habitat has gained tremendous importance in the last decade for the search of such prolific Streptomyces sp. in the context of natural product discovery [21,22]. Given the unusual climatic conditions, the desert have been believed to home for unique potential Streptomyces which are mostly yet to be explored to neutralise the emerging drug-resistant infectious diseases and cancer with their novel bioactive molecules. While considering the recent and past studies [23,24], it becomes clear that the Atacama Desert is focused consistently than other deserts and many more reports to come from other regions.

Extremely Low Cold or Cryoenvironment
Extremely low cold or cryoenvironment is an inexhaustible microbial habitat which has been emphasised by several studies in recent years [25,26]. Because of significant climatic variables in extreme cold habitats, microbes inhabiting there can adapt to harsh conditions which can, in turn, produce novel compounds that are valuable for biotechnology applications [27]. Extreme low cold temperature prevails on Earth in Polar Regions of Arctic and Antarctic, Siberia, Himalayan Mountains, and some permafrost. Bhave et al. [28] reported that Antarctica is the coldest, driest, and windiest continent on Earth. Besides, high UV exposure and low organic and high salt concentrations in soils of Antarctica render them an unusual environment [28]. Arctic is another polar region which has been geographically isolated for millions of years on Earth [29] and has been emphasised by cold winter and cool summer [30], the presence of low nutrient concentrations, high UV radiation, and extreme capricious in day length [27]. e Himalayan cold deserts are reported to have a fragile ecosystem and complex climate [31]. e possible occurrence of high-intensity UV radiation in the lofty mountain is also evidenced in the past study [32]. erefore, to isolate biotechnologically important Streptomyces spp. from the most poorly explored cryoenvironments warrants for new molecules with potential applications. As these environments considered being the greatest diversity of culturable actinomycetes, studies in the recent past revealed the occurrence of novel Streptomyces spp. from the Antarctic ecosystem [33,34].

Volcanic Environment
It is evident that volcanic spring is one of the extreme habitats on Earth and harbours novel microbes as a source of potential drug leads. Volcanic habitats have been neglected over the years and just a few years ago have attracted considerable interest among the researchers. In evidence, it has been documented earlier that volcanic islands have potential harbour microorganisms with distinct genetic features for secondary metabolite production [35]. To date, however, volcanic environments are the least explored and remained one of the understudied extreme environments among the others which provide a tremendous avenue for the search of new bioactive molecules derived from Streptomyces species. Perhaps, until recently, only a very few studies have been performed concerning the isolation of bioactive natural products derived from volcanic environment Streptomyces [35][36][37]. Notably, these studies have been undertaken within the last six years.

Recent Advancements in Cultivation and Classification of Streptomyces from Extreme Environments
Given the bottleneck that exists with real lab isolation strategies of extreme habitat Streptomyces, the new technologies are continually evolving, and actinomycetes researchers have already been made on that front to explore extreme habitats for natural drug discovery by advanced culture-dependent methods. However, it has been proposed that extreme environment microbes do not require extreme culture conditions such as extreme temperature, pH, and pressure [38]. Firstly, to access the novel Streptomyces from extreme habitats will be the key to identify and characterise the molecules with the potential application [10]. In this context, a polyphasic taxonomic approach which includes the biochemical, phenotypic traits and molecular methods in an integrative manner for detecting new Streptomyces sp. from unexploited environments and dereplication may prove worthwhile. ese methods may prevent the reinvestigation of previously reported strains [10].
Until recently, the discovery of bioactive compounds from Streptomyces has been confined to a process of bioassay-guided identification of bioactive fraction from fermented cultures under a defined set of culture conditions. e advanced comprehensive spectroscopy including LC-MS and NMR [39,40], genome mining approach [41], whole-genome sequencing (WGS), next-generation sequencing (NGS), and bioinformatics tools such as Anti-SMASH, BAGEL, SBSPKS and SMURF, and MIBiG led to the isolation of compounds and biosynthetic gene clusters (BGC) from potential strains [42][43][44]. e identified cryptic/ silent gene cluster can be activated for their likely compounds production by changing culture parameters due to their missing environmental cues [42]. Nowadays, reductions in cost and advances in DNA sequencing technology have removed many of the barriers to acquiring the genome sequence of Streptomyces. It has been demonstrated that the available genome sequences of most actinomycetes contain more than 20 BGCs [41]. erefore, the identification of biosynthetic genes from Streptomyces which tend to be colocalized in the chromosome as biosynthetic gene clusters is a promising target to study molecular biology, metabolic engineering, and heterologous expression of new compounds.

Deep-Sea Streptomyces Isolation
Earlier dedicated sampling and culture-dependent studies strongly suggest that Streptomyces species are dwelling in considerable number in deep-sea sediment samples [7,41,[45][46][47][48]. However, until now a very few natural compounds have been isolated from deep-sea-derived Streptomyces. It is because of the limitation in sample collection technology and following isolation methods in real laboratory settings. To effectively collect the samples from deep sea, various advanced collection devices have been made and they have been well documented [49]. e primary devices among these are the remote-operated submarine vehicle (ROVs) [7] and autonomous underwater vehicles (AUVs) [50] that strikingly breakthrough the impediment to access the deep-sea samples. Next, to the sample collection, transportation to the laboratory and therein storage of sediment samples at −80°C for a more extended period find better in the recovering of Streptomyces by preventing fastgrowing bacteria [51]. In the preliminary isolation steps, pretreatment and serial dilutions of sediment samples have been shown to be useful in the enumeration of sporeforming actinobacteria [7,52]. It can also be crucial to use ideal media and seawater in the isolation media [53] and antibiotics such as nystatin and rifampicin to inhibit the fungal and nonfilamentous bacterial growth [54]. Incubation temperature and time have also been known to influence the isolation of deep-sea Streptomyces [52][53][54]. ese innovative and improved technologies paved the way for the exploration of Streptomyces from deep-sea habitats and eventually substantiated by various dedicated studies which involve active culture-dependent microbiological experimentation [41,[46][47][48]. It has also been reported that Streptomyces is the most dominant species in marine sediments with an increase of depth [53]. Notably, to date, many potential natural compounds with unique structures from Streptomyces inhabiting the South China Sea have been isolated than any other deep-sea environments.

Isolation of Streptomyces from Desert
Given published articles so far, it can be explained that the Atacama Desert has gained more interest than other deserts. Studies have demonstrated that extreme habitat of hyperarid or an absolute desert has revealed the presence of culturable and novel Streptomyces [23,55]. Okoro et al. reported that the cultivable percentage of genus Streptomyces is about 91% from the soil sample collected in the Atacama Desert among other actinomycetes [17]. Nonetheless, there was limited number of studies conducted with regard to the isolation of Streptomyces spp. from the ar Desert, India, for their bioactive potential [56][57][58], and notably, no purified compounds with their chemical structures have been reported yet. Recently, Tiwari et al. reported the extracts of Streptomyces spp. isolated from the ar Desert, displaying a International Journal of Microbiology promising inhibitory activity against multidrug-resistantStreptococcus pneumoniae [58]. Selective isolation procedures including serial dilution followed by dry heat at 55°C for 6 minutes for soil samples collected from desert environments are proved to be useful about the isolation of actinomycetes and diversity [17]. It has also shown that pretreatment of the soil sample subject to air drying at 50°C and preincubation at 50°C for an hour yielded Streptomyces on ISP2 media [59]. Hozzien et al. reported that minimal media (MM) containing glucose, yeast extract, and mineral salts which might be useful for selective isolation of actinomycetes including Streptomyces from the desert soil with other media were used [60]. Raffinose-histidine agar supplemented with antibiotics such as cycloheximide (25 µg·ml −1 ) and nystatin (25 µg·ml −1 ) was also found to apply for the isolation of novel species of Streptomyces [61]. Selective media such as Gauze's No. 1 medium [62], humic acid-vitamin agar, SM1 agar, and starch casein agar [22,63] have been used to isolate new Streptomyces sp. which can be used to derive new compounds. Streptomyces violaceusniger strain SPC6 isolated from the Linze Desert has been found to grow in media supplemented with 0 M to 1 M·NaCl, which indicates its adaptation to the arid desert environment [64]. Remarkably, this strain had also shown a high growth rate and short life cycle with just two days at 37°C. It was noted that the optimal growth temperature is ranging from 28°C to 30°C suitable in the context of isolation of Streptomyces species from desert soils [59,65]. e incubation time has been reported ranging from two weeks to four weeks [65][66][67].

Isolation of Streptomyces from Cryoenvironments
Few past studies have demonstrated that the existence of novel Streptomyces spp. from the Antarctic ecosystem and other distinct studies requires to be investigated in such environmental sources [33,34]. Likewise, recently published papers describe novel Streptomyces isolated from Arctic glacier [25,26]. But, till date, no studies described yet concerning novel Streptomyces spp. isolated from Himalayan harsh environments. However, a minimal investigation of this habitat has been undertaken. Several factors are considered for the isolation of Streptomyces from cryoenvironment samples. ey include immediate storage at below 0°C [33], transportation at below 0°C [33], selective isolation media such as tryptone-yeast extract (TY) agar actinomycete isolation medium (1 L of seawater, 18 g of agar, 20 mg/L of cycloheximide, 20 mg/L of nystatin, and 10 mg/L of nalidixic acid), and starch-casein-nitrate agar [33,68,69], incubation temperature between 18°C and 28°C, and incubation time ranging from one week to a month [29,34,69].  [35][36][37], the knowledge of Streptomyces population in volcanic habitat is sparse. It has been postulated that serial dilution of samples, humic acid-vitamin agar (HV) supplemented with nystatin (50 mg·l −1 ) and nalidixic acid (20 mg·l −1 ), and prolonged incubation time over three weeks are proven to be useful in the isolation of Streptomyces sp. from volcanic habitats [70]. Table 1 presents the novel compounds derived from deepsea Streptomyces (DSDS), and their corresponding structures are shown in Figure 1. (1) belonging to the benzoxazole class is produced by Streptomyces sp. NTK 937, isolated from deep sediments collected at a depth of 3814 m near Canary Islands [71]. Caboxamycin displayed antibacterial activity against Gram-positive bacteria, antitumor activity against AGS, MCF7, and HepG2, and enzyme inhibitory activity against phosphodiesterase.  [73]. e presence of the (5, 5) spiro ring system in spiroindimicins B-D might have contributed moderate antitumor activities [73]. e inactivation of halogenase gene spmH in Streptomyces sp. SCSIO 03032 yielded two new bisindole alkaloids named spiroindimicins G (8) and H (9) [84]. Spiroindimicin G showed moderate cytotoxic activities against four cancer cell lines including SF-268, MCF-7, HepG2, and A549 with IC 50 values of 16.09 ± 1.26, 19.11 ± 2.23, 13.57 ± 0.24, and 10.28 ± 0.14 μM, respectively. Spiroindimicin H also displayed moderate inhibitory activity against SF-268, MCF-7,      [75]. It has shown that grincamycin F differs from grincamycin primarily in the structure of its enlarged aglycone, which contains a six-membered lactone ring and a hydroxybenzene in addition to the typical angucycline four-ring system. e investigators revealed that the enlarged aglycone of grincamycin might eliminate its cytotoxicity properties [75].

Pyrroloiminoquinone. Ammosamides
Streptomyces lusitanus SCSIO LR32, isolated from the South China Sea at a depth of 3370 m, yielded two new compounds named grincamycins G (20) and H (21) belonging to rearranged linear angucycline glycosides. Intriguingly, the new compound grincamycin H showed cytotoxicity on Jurkat T cells with an IC 50 value of 3.0 µm. However, grincamycin G exhibited no cytotoxic activity at the concentration of 20 µm on Jurkat T cells [81]. e authors ascertain that aglycone moiety may also have a role in the derivation of chemical and biological diversity of angucycline in addition to the sugar unit.
Streptomyces sp. SCSIO 11594, isolated from a deep-sea sediment sample collected at a depth of 2403 m in the South China Sea, yielded two new C-glycoside angucycline antibiotics, namely, marangucyclines A (22) and B (23) together with three known compounds dehydroxyaquayamycin, undecylprodigiosin, and metacycloprodigiosin [47]. All the compounds were tested for cytotoxicity activity against four cancer cell lines A594, CNE2, HepG2, and MCF-7. Marangucycline B and undecylprodigiosin displayed promising cytotoxic activity against all cancer lines. e investigators reported that marangucycline B presented 20-fold more cytotoxic activity than cisplatin, while undecylprodigiosin showed tenfold more cytotoxicity than cisplatin which is used as positive control. e keto sugar of marangucycline B is believed to be a possible reason for significant cytotoxicity activity with IC 50 values ranging from 0. 24 [76]. It has been predicted that the absence of C-32 hydroxyl group in lobophorins E and F when compared with lobophorin B significantly enhances their antimicrobial properties against S. aureus ATCC 29213. Lobophorin E displayed antibacterial activity against Staphylococcus aureus ATCC 29213 with the MIC value of 32 µg/mL. It has also been inferred from the structures that the presence of the terminal sugar moiety (4-O-L-digitoxose, sugar C) is disadvantageous for the antimicrobial and antitumor property. e investigators suggest that the presence of the nitro-sugar moiety is critical and change of sugar moieties will yield natural products with defined or altered biological activity [76].
Streptomyces sp. 12A35, recovered from a deep-sea sediment sample of South China Sea at a depth 2134 m, yielded two new spirotetronate antibiotics, namely, lobophorins H (28) and I (29) together with three known analogues, O-β-kijanosyl-(1 ⟶ 17)-kijanolide and lobophorins B and F [46]. Lobophorins H and I did not exhibit inhibitory activity against Gram-negative bacteria (E. coli) and fungi (C. with MIC values of 6.25, 50, and 50 μg/mL, respectively. From the results, it was proposed that the monosaccharide units might play an essential role in the antimicrobial activity of lobophorins. e investigators also suggested that the increasing amount of monosaccharide units resulted in increased inhibitory activity. us, the potent antibacterial activity efficiency of lobophorin I and H against Grampositive bacteria may provide the new candidature for anti-infective drug development [46]. Streptomyces sp. M-207, isolated from the deep-sea coral Lophelia pertusa collected at 1800 m depth in the central Cantabrian Sea, was found to produce a novel compound belonging to lobophorin family, designated as lobophorin K (30). Remarkably, lobophorin K exhibited cytotoxic activity on a human breast adenocarcinoma cell line (MCF-7), a human pancreatic carcinoma cell line (MiaPaca-2), and a human immortalised hepatocyte cell line (THLE-2) with IC 50 values of 23.0 ± 8.9, 34.0 ± 85.1, and 6.3 ± 8.2 µM, respectively [83]. Lobophorin K had also displayed a moderate and selective antibacterial activity against pathogenic methicillin-sensitive Staphylococcus aureus EPI1167 MSSA.

Hydroxyquinaldic Acid. Streptomyces cyaneofuscatus
M-157, isolated from the deep sea at 1800 m depth in the central Cantabrian Sea, was found to produce a novel antibiotic 3-hydroxyquinaldic acid derivative (31). e compound exhibited cytotoxic activity on HepG2 with an IC 50 value of 51.5 μM [85].  [48]. e authors also proposed that the presence of the methyl group at C-2 in anthracimycin B could be responsible for its potent antimicrobial activity.  (37) is a new lasso peptide (15 amino-acid) obtained from Streptomyces sp. SNJ013. e producing strain was recovered from a sediment sample collected at a depth of 138 m off the coast of Sungsanpo on Jeju Island, Republic of Korea. Sungsanpin showed inhibitory activity in a cell invasion assay for the lung cancer cell line A549 [78]. Sungsanpin is currently in preclinical trials for cancer treatment [50].

Peptide. Sungsanpin
Two new linear peptides named ahpatinin Ac (38) and ahpatinin Pr (39) obtained together with the known ahpatinin iBu, pepstatin Ac, pepstatin Pr, and pepsinostreptin from Streptomyces sp. ACT232, isolated from deep-sea sediment collected at a depth of 1174 m in the Sagami Bay, Japan [79]. All the compounds tested in this study displayed moderate inhibitory activity against cathepsin B, with IC 50 values ranging from 10 to 29 μM. Cathepsin B had been reported to be a promising target for anticancer agents [90]. It was also identified that ahpatinin Ac and ahpatinin Pr had structural similarity with pepstatin, which is a potent aspartic protease inhibitor. By structural similarity, ahpatinin Ac, ahpatinin Pr, pepstatin Ac, and pepstatin Pr inhibited pepsin with IC 50 values between 11 and 50 nM [79].
Desotamides B-D (40)(41)(42) are new antibiotics belonging to the cyclohexapeptides class and together with a known desotamide obtained from a deep-sea-derived Streptomyces scopuliridis SCSIO ZJ46, recovered from sediment sample collected at a depth of 3536 m in the South China Sea [80]. e investigators reported that desotamide and desotamide B had shown similar antimicrobial activities against Staphylococcus aureus ATCC 29213, Streptococcus pneumoniae NCTC 7466, and MRSE shhs-E1 with MIC values of 16.0, 12.5, and 32.0 μg/mL, respectively. On the other hand, all the tested compounds failed to display cytotoxicities (IC 50 > 100 μM) against four human tumour cell lines SF-268, MCF-7, NCI-H460, and HepG-2 [80]. erefore, the compounds are proposed to be promising candidatures for antibacterial drug development. e investigators suggested that the presence of Trp moiety in their defined structure is significant and might contribute to their antibacterial activity properties and made it a vital structure-activity relationship for developing new drug leads against bacterial infections.
Genome mining of Streptomyces atratus SCSIO ZH16 yielded a new antibiotic atratumycin (43) belonging to cyclodepsipeptide. e strain was isolated from the deep-sea sediment collected at a depth of 3536 m in the South China Sea. Atratumycin exhibited inhibitory activities against Mycobacteria tuberculosis H37Ra and H37Rv with MICs of 3.8 and 14.6 μM, respectively [41]. e authors ascertain that atratumycin might be an excellent drug lead to be developed against tuberculosis.

Novel Antibacterial and Anticancer Compounds from Cultured Desert Streptomyces. Cytotoxic and antibacterial
International Journal of Microbiology molecules derived from desert Streptomyces with distinct bioactivities to date are listed in Table 1, and their corresponding structures are shown in Figure 2.
Chaxapeptin (45) is a new lasso peptide antibiotic isolated from the fermentation broth of Streptomyces leeuwenhoekii strain C58, recovered from the Atacama Desert [88]. Chaxapeptin showed inhibitory activity in a cell invasion assay with human lung cancer cell line A549. Besides, this molecule has also shown weak antibacterial activity against Gram-positive bacteria, Staphylococcus aureus, and Bacillus subtilis with the MIC values of 30−35 μg mL −1 [88].
Chaxamycins A-D (49-52) is a new ansamycin-type polyketides antibiotics isolated from the fermentation broth of Streptomyces sp. strain C34, recovered from a soil sample collected in the Atacama Desert [23]. Among the compounds tested, chaxamycin D showed promising selective antibacterial activity against S. aureus ATCC 25923 and a panel of MRSA clinical isolates.
Abenquines A-D (56-59) is a new aminoquinone-type antibiotics isolated from the fermentation broth of Streptomyces sp. strain DB634, recovered from a soil sample collected in the Atacama Desert [59]. All of the compounds tested displayed moderate antibacterial activity against Bacillus subtilis, dermatophytic fungi. Further, abenquines A and D showed moderate enzyme inhibitory activity against phosphodiesterase type 4b (PDE4b).
Asenjonamides A-C (60-62) is a new polyketide antibiotic isolated from the fermentation broth of Streptomyces asenjonii KNN 42.f, recovered from a soil sample collected in the hyper-arid Atacama Desert [21]. Asenjonamides A-C displayed significant antibacterial activity against Grampositive strains of S. aureus, B. subtilis, and E. faecalis. Remarkably, asenjonamides C showed potent activity against Gram-negative E. coli to tetracycline (positive control).

Novel Antibacterial and Anticancer Compounds from
Cultured Low Cold Environment Streptomyces. Table 1 and Figure 3(a) show the new bioactive molecules isolated from cryoenvironment-derived Streptomyces.
Streptomyces sp. ART5, isolated from a sediment sample collected in the East Siberian continental margin of Arctic Ocean, yielded two benzoxazine antibiotics named arcticoside (69) and C-1027 chromophore-V (70) together with C-1027 chromophore-III and fijiolides A and B [69]. Arcticoside and C-1027 chromophore-V showed inhibitory activity against Candida albicans isocitrate lyase. But C-1027 chromophore-V exhibited significant cytotoxicity against breast carcinoma MDA-MB231 cells and colorectal carcinoma cells (line HCT-116), with the IC 50 values of 0.9 and 2.7 μM, respectively [69].

Novel Antibacterial and Anticancer Compounds from
Cultured Volcanic Environment Streptomyces. Table 1 and Figure 3(b) present the new bioactive molecules isolated from cryoenvironment-derived Streptomyces.
Ohmyungsamycins A (71) and B (72) are new cyclic peptides isolated from the fermentation broth of Streptomyces sp. SNJ042, recovered from Jeju, a volcanic island in the Republic of Korea [35]. Ohmyungsamycin A showed potent cytotoxicity against various cancer cell lines such as HCT-116, A549, SNU-638, MDA-MB-231, and SKHEP-1 cells, with IC 50 values between 359 and 816 nM. But ohmyungsamycin B exhibited weak cytotoxicity against the tested cancer cells, with IC 50 values ranging from 12.4 to 16.8 μM. Besides, ohmyungsamycin A exhibited significant inhibitory activity against selected Gram-positive and Gramnegative bacteria [35]. However, ohmyungsamycin B displayed weak antibacterial activity than ohmyungsamycin A. Further, to prove the structure and functional activity, the authors proposed that the presence of additional N-methyl group at the terminus of ohmyungsamycin B could be the possible reason for decreased bioactivity.
Ulleungdin (73)   International Journal of Microbiology Ulleung Island (a small volcanic island), Korea [37]. Ulleungdin exhibited significant inhibitory activities against cancer cell invasion and migration of human lung carcinoma A549 cells. e authors ascertain that ulleungdin has a low similarity (33.3%) with chaxapeptin and sungsanpin which were reported to have cancer cell invasion and migration activities. Moreover, the length of the amino acid or the size of the macrolactam ring in ulleungdin might be attributed to the anti-invasion activities [37].

Biosynthetic Gene Clusters
Biosynthetic gene cluster (BGC) containing a group of genes is responsible for the production of many of the bioactive metabolites in actinomycetes. It has been reported that gene clusters are likely to encode natural product biosynthetic pathways in sequenced microbial genomes [91]. In general, the size of the biosynthetic gene clusters in Streptomyces chromosome ranges from a few kb to 100 kb [92,93]. It has been demonstrated that nonribosomal peptide synthetases (NRPS) and polyketide synthase (PKS) are known to be involved in the synthesis of many of the bioactive metabolites in actinomycetes [94]. Many gene clusters till date have been identified in Streptomyces spp., either of polyketide synthases (PKS), nonribosomal peptide synthetases (NRPS), or the hybrid PKS-NRPS.

Polyketide Synthases
Type I PKS gene cluster consists of multifunctional enzyme modules and at least three domains corresponding to a ketosynthase (KS), an acyltransferase (AT), and an acyl     carrier protein (ACP) which attribute for the selection and condensation (Claisen type) of the correct extender unit of polyketide chain [94]. Besides, type I gene cluster contains genes such as ketoreductase (KR), dehydratase (DH), and enoyl reductase (EH) for specialised functions [95]. Type I gene cluster has been classified into two subclasses such as modular type I PKS and iterative type I PKS. In iterative type I PKS gene cluster, a single module attributes for all functions that are governing the polyketide chain elongation, whereas in modular type I gene cluster, one extension cycle is regulated by one particular PKS module. Type II PKS gene cluster contains a minimal PKS that comprises of three enzymes such as two keto acyl synthase subunits (KSα and KSβ) and an acyl carrier protein (ACP). ese enzymes have been reported to putatively control the choice of the starter unit and the number of extenders used in the synthesis of nascent polyketide chain [96].

Nonribosomal Peptide Synthetases
It has been documented that nonribosomal peptide synthetases (NRPSs) are mega enzymes usually with a multimodular structure, which catalyse the nonribosomal assembly of peptides from proteinogenic and nonproteinogenic amino acids [97,98]. Schwarzer and Marahiel reported that an NRPS module usually contains an adenylation domain (A-domain), a peptidyl carrier protein domain (PCP-domain), and a condensation domain (Cdomain) [99]. A-domain was determined to select the cognate amino acid (AA) from the pool of available substrates and generates the corresponding aminoacyl adenylate using ATP [100]. PCP-domain involves in the thioesterification of the activated amino acid. C-domain performs transpeptidation between the upstream and downstream peptidyl and aminoacyl thioesters to elongate the growing peptide chain. Also, it was found that a chain-terminating thioesterase domain (TE-domain) that is responsible for the detachment of the mature polypeptide [101]. ere is involvement of several hundred substrates for protein synthesis by NRPSs in contrast to 20 amino acids which is confined to normal protein synthesis [97]. Interestingly, the biological functions of NRPS via synthesised compounds associated with the chemical nature of peptide which is correlated with the gene sequence [98].

Hybrid PKS-NRPS
e combination of PKS and NRPS modules may be present as a hybrid PKS-NRPS gene cluster [102].

Characterised Gene Clusters from
Extreme Streptomyces ough advances in genome sequencing, to date, very few gene clusters have been isolated and characterised by extreme environment Streptomyces and they are described below. Notably, several studies have focused on gene clusters from deep-sea Streptomyces and exploited for their biosynthetic pathways. e type I PKS gene cluster governing synthesis of lobophorin from deep-sea Streptomyces sp. 12A35 was first isolated and exploited [103]. During the 2015s, a significant number of gene clusters from deep-sea Streptomyces sparked interest. e NRPS type gene cluster for marfomycin biosynthesis has been identified from Streptomyces drozdowiczii SCSIO 10141 [104]. Another study has demonstrated that the identification of NRPS type gene cluster responsible for the biosynthesis of desotamides by a deep-sea Streptomyces scopuliridis SCSIO ZJ46 [105]. e cryptic gene cluster is about 25 kb in size that is responsible for the biosynthesis of fredericamycin A (FDM A) from the mutant strain genome of Streptomyces somaliensis SCSIO ZH66 RIF1 which was identified by Zhang et al. [106]. e type I PKS heronamide gene cluster from deep-sea Streptomyces sp. SCSIO 03032 was isolated and characterised [107]. Recently, Ma and coworkers identified spiroindimicin (SPM) gene cluster from Streptomyces sp. SCSIO 03032 [108]. A recent study explored the atratumycin biosynthetic gene cluster from Streptomyces atratus SCSIO ZH16 [41]. e gene clusters for chaxamycin, chaxalactin, and chaxapeptin biosynthesis have been identified from S. leeuwenhoekii C34 recovered from the Atacama Desert [109]. A recent study demonstrated the gene cluster responsible for ulleungdin from Streptomyces sp. KCB13F003 isolated from Ulleung volcanic Island [37].

Conclusion and Future Remarks
In conclusion, to date reports suggest that extreme Streptomyces-derived natural compounds with their structureactivity relationship (SAR) have an incredible source to develop future drugs against cancer and bacterial infections.
us, it becomes clear that potential Streptomyces are existed in all the extreme environments so far studied. Furthermore, the future identification of various gene clusters from extreme habitat-derived Streptomyces unlocks the different hidden natural products biosynthetic machinery in more detail and would make it possible for combinatorial biosynthesis to expand more natural products with distinct structural diversity. Furthermore, the whole-genome sequence (WGS) analysis of the potent strains would provide an insight into how these strains adapt to extreme environmental conditions and different regulatory pathways that are associated with bioactive compound productions.
ough there is evidence that interest sharply decreased in natural product discovery in the past decades, the future would largely depend on academic and biotech industries collaboration. e present review also highlighted that research on extreme habitat Streptomyces-derived natural products constantly continued to grow in the specific geographical location especially in the South China Sea, Atacama Desert, Arctic, and Korean volcanic regions. It is the hope that additional report will become available from other extreme areas over time in respect of novel natural compounds. erefore, the authors ascertained herein that Streptomyces from extreme habitat will be an excellent source of novel antibiotics with distinct biological activities in the fight against bacterial infections and cancer. 16 International Journal of Microbiology